Updated on 2023/09/20

写真a

 
Seiya Yokoyama
 
Organization
Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area Graduate School of Medical and Dental Sciences Advanced Therapeutics Course Oncology Assistant Professor
Title
Assistant Professor

Degree

  • Ph.D. ( 2009.9   Kagoshima University )

Research Interests

  • Epigenetics

  • DNA methylation

  • Machine learning

  • PDAC

  • Prognosis prediction

  • Machine learning

  • Epigenetics

  • Early Diagnosis

  • DNA methylation

Research Areas

  • Life Science / Tumor diagnostics and therapeutics  / 胆管癌

  • Life Science / Genome biology  / DNAメチル化

  • Life Science / System genome science  / 判別モデル

  • Life Science / Tumor diagnostics and therapeutics  / Pancreas and Bile Duct cancer

  • Life Science / Experimental pathology

Education

  • Kagoshima University

    2004.4 - 2008.3

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    Country: Japan

  • Kagoshima University   Biochemical Science and Technology

    1997.4 - 2002.3

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    Country: Japan

Research History

  • Kagoshima University   Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area Graduate School of Medical and Dental Sciences Advanced Therapeutics Course Oncology Field of pathology   Assistant Professor

    2017.4

  • University of Nebraska Medical Center   Eppley Institute for Research in Cancer   Postdoctoral Research Fellow

    2015.3 - 2017.3

  • Kagoshima University   Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area Graduate School of Medical and Dental Sciences Advanced Therapeutics Course   Assistant Professor

    2012.4 - 2017.3

  • Kagoshima University   Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area Graduate School of Medical and Dental Sciences Advanced Therapeutics Course   Researcher

    2009.4 - 2012.3

Professional Memberships

  • 日本癌学会

    2009.10

  • 日本病理学会

    2009.10

Studying abroad experiences

  • 2015.4 - 2017.3   University of Nebraska Medical Center   Postdoctoral research fellow

 

Papers

  • Higashi Y, Nakamura K, Takaoka R, Tani M, Noma Y, Mori K, Yamashiro K, Yokoyama S, Hamada T, Sugiura T .  Identification of Neck Lymph Node Metastasis-Specific microRNA-Implication for Use in Monitoring or Prediction of Neck Lymph Node Metastasis. .  Cancers15 ( 15 )   2023.7Identification of Neck Lymph Node Metastasis-Specific microRNA-Implication for Use in Monitoring or Prediction of Neck Lymph Node Metastasis.Reviewed

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    DOI: 10.3390/cancers15153769

    PubMed

  • Ikumi Kitazono, Toshiaki Akahane, Seiya Yokoyama, Yusuke Kobayashi, Shinichi Togami, Shintaro Yanazume, Takashi Tasaki, Hirotsugu Noguchi, Kazuhiro Tabata, Hiroaki Kobayashi, Akihide Tanimoto .  "Surface epithelial slackening" pattern in endometrioid carcinoma: A morphological feature for differentiating the POLE mutation-subtype from the no specific molecular profile subtype. .  Pathology, research and practice247   154563 - 154563   2023.5"Surface epithelial slackening" pattern in endometrioid carcinoma: A morphological feature for differentiating the POLE mutation-subtype from the no specific molecular profile subtype.Reviewed International journal

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    Endometrial cancers are classified into mismatch repair (MMR) deficient- (MMRd), p53 mutation- (p53mut), DNA polymerase epsilon (POLE) mutation (POLEmut), and no specific molecular profile (NSMP) subtypes according to The Cancer Genome Atlas (TCGA). The distinction between POLEmut and NSMP subtypes is made on the basis of molecular analysis because the specific histological and immunohistochemical features of these two subtypes are still unknown. In this study, we analyzed histological features by scoring the presence of a mucinous pool, giant cells, clear cells, keratinization, neutrophilic abscess, and surface proliferating pattern in 82 cases of endometrial cancers in which an integrative diagnosis was confirmed by immunohistochemistry and genomic profiles showing POLE mutations, tumor mutation burden, and microsatellite instability. In contrast to the hierarchical branching of micropapillary proliferation observed in serous carcinoma, POLEmut-subtype endometrioid carcinomas often showed a surface epithelial slackening (SES) pattern in the tumor cells facing the uterine surface. The POLEmut subtype exhibited higher scores for clear cells and SES patterns than the other three subtypes. The scores for giant cells, clear cells, and the SES pattern were significantly higher in the POLEmut subtype than in the NSMP subtype, suggesting that these morphometric parameters are useful for differentiating POLEmut- and NSMP-subtype endometrioid carcinomas, although genomic profiling is still necessary for a definite molecular diagnosis.

    DOI: 10.1016/j.prp.2023.154563

    PubMed

  • Taiji Hamada, Michiyo Higashi, Seiya Yokoyama, Toshiaki Akahane, Masanori Hisaoka, Hirotsugu Noguchi, Tatsuhiko Furukawa, Akihide Tanimoto .  MALAT1 functions as a transcriptional promoter of MALAT1::GLI1 fusion for truncated GLI1 protein expression in cancer. .  BMC cancer23 ( 1 ) 424 - 424   2023.5MALAT1 functions as a transcriptional promoter of MALAT1::GLI1 fusion for truncated GLI1 protein expression in cancer.Reviewed International journal

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    BACKGROUND: The long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a cancer biomarker. Furthermore, fusion of the MALAT1 gene with glioma-associated oncogene 1 (GLI1) is a diagnostic marker of plexiform fibromyxoma and gastroblastoma; however, the function of this fusion gene remains unexplored. METHOD: In this study, we elucidate the structure and function of the MALAT1::GLI1 fusion gene. To this end, we determined a transcriptional start site (TSS) and promoter region for truncated GLI1 expression using rapid amplification of the 5' cDNA end and a luciferase reporter assay in cultured cells transfected with a plasmid harboring the MALAT1::GLI1 fusion gene. RESULTS: We found that the TATA box, ETS1 motif, and TSS were located in MALAT1 and that MALAT1 exhibited transcriptional activity and induced expression of GLI1 from the MALAT1::GLI1 fusion gene. Truncated GLI1, lacking SUMOylation and SUFU binding sites and located in the nucleus, upregulated mRNA expression of GLI1 target genes in the hedgehog signaling pathway. CONCLUSIONS: We demonstrate a distinct and alternative function of MALAT1 as a transcriptional promoter for expression of the MALAT1::GLI1 fusion gene. Our findings will aid future research on MALAT1 and its fusion gene partners.

    DOI: 10.1186/s12885-023-10867-6

    PubMed

  • Hirofumi Yoshino, Seiya Yokoyama, Motoki Tamai, Shunsuke Okamura, Sayaka Iizasa, Takashi Sakaguchi, Yoichi Osako, Satoru Inoguchi, Ryosuke Matsushita, Yasutoshi Yamada, Masayuki Nakagawa, Shuichi Tatarano, Akihide Tanimoto, Hideki Enokida .  Characterization and treatment of gemcitabine- and cisplatin-resistant bladder cancer cells with a pan-RAS inhibitor. .  FEBS open bio13 ( 6 ) 1056 - 1066   2023.4Characterization and treatment of gemcitabine- and cisplatin-resistant bladder cancer cells with a pan-RAS inhibitor.Reviewed International journal

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    Combination chemotherapy with gemcitabine and cisplatin (GC) is recommended as the primary treatment for advanced bladder cancer (BC). However, the benefits of this approach are limited owing to the acquisition of drug resistance. Here, we found report that gemcitabine-resistant and cisplatin-resistant BCs do not exhibit cross-resistance, and that these BCs exhibit different mRNA patterns, as revealed using RNA sequence analysis. To overcome drug resistance, we used the newly developed pan-RAS inhibitor Compound 3144. Compound 3144 inhibited cell viability through suppression of RAS-dependent signaling in gemcitabine- and cisplatin-resistant BCs. RNA sequencing revealed that several genes and pathways, particularly those related to the cell cycle, were significantly downregulated in Compound 3144-treated BCs. These findings provide insights into potential therapeutic strategies for treating BC.

    DOI: 10.1002/2211-5463.13616

    PubMed

  • Nayuta Higa, Toshiaki Akahane, Seiya Yokoyama, Ryutaro Makino, Hajime Yonezawa, Hiroyuki Uchida, Tomoko Takajo, Mari Kirishima, Taiji Hamada, Naoki Noguchi, Ryosuke Otsuji, Daisuke Kuga, Shohei Nagasaka, Hitoshi Yamahata, Junkoh Yamamoto, Koji Yoshimoto, Akihide Tanimoto, Ryosuke Hanaya .  Favorable prognostic impact of phosphatase and tensin homolog alterations in wild-type isocitrate dehydrogenase and telomerase reverse transcriptase promoter glioblastoma. .  Neuro-oncology advances5 ( 1 ) vdad078   2023.1Favorable prognostic impact of phosphatase and tensin homolog alterations in wild-type isocitrate dehydrogenase and telomerase reverse transcriptase promoter glioblastoma.Reviewed International journal

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    BACKGROUND: Telomerase reverse transcriptase promoter (TERTp) mutations are a biological marker of glioblastoma; however, the prognostic significance of TERTp mutational status is controversial. We evaluated this impact by retrospectively analyzing the outcomes of patients with isocitrate dehydrogenase (IDH)- and TERTp-wild-type glioblastomas. METHODS: Using custom next-generation sequencing, we analyzed 208 glioblastoma samples harboring wild-type IDH. RESULTS: TERTp mutations were detected in 143 samples (68.8%). The remaining 65 (31.2%) were TERTp-wild-type. Among the TERTp-wild-type glioblastoma samples, we observed a significant difference in median progression-free survival (18.6 and 11.4 months, respectively) and overall survival (not reached and 15.7 months, respectively) in patients with and without phosphatase and tensin homolog (PTEN) loss and/or mutation. Patients with TERTp-wild-type glioblastomas with PTEN loss and/or mutation were younger and had higher Karnofsky Performance Status scores than those without PTEN loss and/or mutation. We divided the patients with TERTp-wild-type into 3 clusters using unsupervised hierarchical clustering: Good (PTEN and TP53 alterations; lack of CDKN2A/B homozygous deletion and platelet-derived growth factor receptor alpha (PDGFRA) alterations), intermediate (PTEN alterations, CDKN2A/B homozygous deletion, lack of PDGFRA, and TP53 alterations), and poor (PDGFRA and TP53 alterations, CDKN2A/B homozygous deletion, and lack of PTEN alterations) outcomes. Kaplan-Meier survival analysis indicated that these clusters significantly correlated with the overall survival of TERTp-wild-type glioblastoma patients. CONCLUSIONS: Here, we report that PTEN loss and/or mutation is the most useful marker for predicting favorable outcomes in patients with IDH- and TERTp-wild-type glioblastomas. The combination of 4 genes, PTEN, TP53, CDKN2A/B, and PDGFRA, is important for the molecular classification and individual prognosis of patients with IDH- and TERTp-wild-type glioblastomas.

    DOI: 10.1093/noajnl/vdad078

    PubMed

  • Taiji Hamada, Seiya Yokoyama, Toshiaki Akahane, Kei Matsuo, Akihide Tanimoto .  Genome Editing Using Cas9 Ribonucleoprotein Is Effective for Introducing PDGFRA Variant in Cultured Human Glioblastoma Cell Lines. .  International journal of molecular sciences24 ( 1 )   2022.12Genome Editing Using Cas9 Ribonucleoprotein Is Effective for Introducing PDGFRA Variant in Cultured Human Glioblastoma Cell Lines.Reviewed International journal

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    Many variants of uncertain significance (VUS) have been detected in clinical cancer cases using next-generation sequencing-based cancer gene panel analysis. One strategy for the elucidation of VUS is the functional analysis of cultured cancer cell lines that harbor targeted gene variants using genome editing. Genome editing is a powerful tool for creating desired gene alterations in cultured cancer cell lines. However, the efficiency of genome editing varies substantially among cell lines of interest. We performed comparative studies to determine the optimal editing conditions for the introduction of platelet-derived growth factor receptor alpha (PDGFRA) variants in human glioblastoma multiforme (GBM) cell lines. After monitoring the copy numbers of PDGFRA and the expression level of the PDGFRα protein, four GBM cell lines (U-251 MG, KNS-42, SF126, and YKG-1 cells) were selected for the study. To compare the editing efficiency in these GBM cell lines, the modes of clustered regularly interspaced short palindromic repeat (CRISPR)-associated protein 9 (Cas9) delivery (plasmid vs. ribonucleoprotein (RNP)), methods of transfection (lipofection vs. electroporation), and usefulness of cell sorting were then evaluated. Herein, we demonstrated that electroporation-mediated transfer of Cas9 with single-guide RNA (Cas9 RNP complex) could sufficiently edit a target nucleotide substitution, irrespective of cell sorting. As the Cas9 RNP complex method showed a higher editing efficiency than the Cas9 plasmid lipofection method, it was the optimal method for single-nucleotide editing in human GBM cell lines under our experimental conditions.

    DOI: 10.3390/ijms24010500

    PubMed

  • Nayuta Higa, Toshiaki Akahane, Seiya Yokoyama, Hajime Yonezawa, Hiroyuki Uchida, Shingo Fujio, Mari Kirishima, Kosuke Takigawa, Nobuhiro Hata, Keita Toh, Junkoh Yamamoto, Ryosuke Hanaya, Akihide Tanimoto, Koji Yoshimoto .  Molecular Genetic Profile of 300 Japanese Patients with Diffuse Gliomas Using a Glioma-tailored Gene Panel. .  Neurologia medico-chirurgica62 ( 9 ) 391 - 399   2022.9Molecular Genetic Profile of 300 Japanese Patients with Diffuse Gliomas Using a Glioma-tailored Gene Panel.Reviewed

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    Rapid technological advances in molecular biology, including next-generation sequencing, have identified key genetic alterations in central nervous system (CNS) tumors. Accordingly, the fifth edition of the World Health Organization (WHO) CNS tumor classification was published in 2021. We analyzed 303 patients with diffuse glioma using an amplicon-based glioma-tailored gene panel for detecting 1p/19q codeletion and driver gene mutations such as IDH1/2, TERTp, EGFR, and CDKN2A/B on a single platform. Within glioblastomas (GBMs), the most commonly mutated genes were TERTp, TP53, PTEN, NF1, and PDGFRA, which was the most frequently mutated tyrosine kinase receptor in GBM, followed by EGFR. The genes that most commonly showed evidence of loss were PTEN, CDKN2A/B, and RB1, whereas the genes that most commonly showed evidence of gain/amplification were EGFR, PDGFRA, and CDK4. In 22 grade III oligodendroglial tumors, 3 (14%) patients had CDKN2A/B homozygous deletion, and 4 (18%) patients had ARID1A mutation. In grade III oligodendroglial tumors, an ARID1A mutation was associated with worse progression-free survival. Reclassification based on the WHO 2021 classification resulted in 62.5% of grade II/III isocitrate dehydrogenase (IDH) -wildtype astrocytomas being classified as IDH-wildtype GBM and 37.5% as not elsewhere classified. In summary, our glioma-tailored gene panel was applicable for molecular diagnosis in the WHO 2021 classification. In addition, we successfully reclassified the 303 diffuse glioma cases based on the WHO 2021 classification and clarified the genetic profile of diffuse gliomas in the Japanese population.

    DOI: 10.2176/jns-nmc.2022-0103

    PubMed

  • Sieya Yokoyama, Hiromichi Iwaya, Toshiaki Akahane, Taiji Hamada, Michiyo Higashi, Shinichi Hashimoto, Shiroh Tanoue, Takao Ohtsuka, Akio Ido, Akihide Tanimoto .  Sequential evaluation of MUC promoter methylation using next‐generation sequencing‐based custom‐made panels in liquid‐based cytology specimens of pancreatic cancer .  Diagnostic Cytopathology50 ( 11 ) 499 - 507   2022.8Reviewed International journal

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Wiley  

    BACKGROUND: As liquid-based cytology (LBC) specimens preserve high-quality DNA, clinical sequencing of LBC specimens using next-generation sequencing (NGS) is becoming a common strategy. This study aimed to evaluate the feasibility of NGS-based custom-made panels for evaluating MUC promoter methylation in LBC specimens. METHODS: Thirty-one patients with pancreatic cancer were enrolled in the study. Cancer tissue samples were obtained using endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/FNB). LBC, formalin-fixed paraffin-embedded (FFPE), and fresh frozen specimens were prepared for DNA extraction after pathological diagnosis. These specimens were then subjected to NGS analysis using custom-made cancer gene screening and methylation panels comprising 28 cancer-related genes and 13 gene promoter regions, including MUC1, MUC2, and MUC4. RESULTS: The success rate of NGS using the cancer gene panel was comparable among the LBC, FFPE, and frozen specimens, and the presence of cancer cell-derived somatic mutations in each specimen was confirmed. The specimens were then tested using a methylation panel that revealed the sequential methylation status of CpG islands located in the promoter regions of MUC genes. The methylation status results obtained from LBC specimens were almost comparable with those from FFPE and frozen specimens. CONCLUSIONS: MUC and other gene methylation analyses using an NGS-based panel were successfully performed in residual LBC specimens obtained by EUS-FNA/FNB. Therefore, this approach provides an alternative source of molecular tests for gene mutations and methylation, especially in the pancreatic cancers, which are often unresectable and unsuitable for obtaining FFPE specimens.

    DOI: 10.1002/dc.25022

    PubMed

    Other Link: https://onlinelibrary.wiley.com/doi/full-xml/10.1002/dc.25022

  • Nayuta Higa, Toshiaki Akahane, Taiji Hamada, Hajime Yonezawa, Hiroyuki Uchida, Ryutaro Makino, Shoji Watanabe, Tomoko Takajo, Seiya Yokoyama, Mari Kirishima, Kei Matsuo, Shingo Fujio, Ryosuke Hanaya, Akihide Tanimoto, Koji Yoshimoto .  Distribution and favorable prognostic implication of genomic EGFR alterations in IDH-wildtype glioblastoma. .  Cancer medicine12 ( 1 ) 49 - 60   2022.6Distribution and favorable prognostic implication of genomic EGFR alterations in IDH-wildtype glioblastoma.Reviewed International journal

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    BACKGROUND: We aimed to evaluate the mutation profile, transcriptional variants, and prognostic impact of the epidermal growth factor receptor (EGFR) gene in isocitrate dehydrogenase (IDH)-wildtype glioblastomas (GBMs). METHODS: We sequenced EGFR, evaluated the EGFR splicing profile using a next-generation sequencing oncopanel, and analyzed the outcomes in 138 grade IV IDH-wildtype GBM cases. RESULTS: EGFR mutations were observed in 10% of GBMs. A total of 23.9% of the GBMs showed EGFR amplification. Moreover, 25% of the EGFR mutations occurred in the kinase domain. Notably, EGFR alterations were a predictor of good prognosis (p = 0.035). GBM with EGFR alterations was associated with higher Karnofsky Performance Scale scores (p = 0.014) and lower Ki-67 scores (p = 0.005) than GBM without EGFR alterations. EGFRvIII positivity was detected in 21% of EGFR-amplified GBMs. We identified two other EGFR variants in GBM cases with deletions of exons 6-7 (Δe 6-7) and exons 2-14 (Δe 2-14). In one case, the initial EGFRvIII mutation transformed into an EGFR Δe 2-14 mutation during recurrence. CONCLUSIONS: We found that the EGFR gene profiles of GBM differ among cohorts and that EGFR alterations are good prognostic markers of overall survival in patients with IDH-wildtype GBM. Additionally, we identified rare EGFR variants with longitudinal and temporal transformations of EGFRvIII.

    DOI: 10.1002/cam4.4939

    PubMed

  • Mari Kirishima, Seiya Yokoyama, Kei Matsuo, Taiji Hamada, Michiko Shimokawa, Toshiaki Akahane, Tomoyuki Sugimoto, Hirohito Tsurumaru, Matsujiro Ishibashi, Yuko Mataki, Takao Ootsuka, Mitsuharu Nomoto, Chihiro Hayashi, Akihiko Horiguchi, Michiyo Higashi, Akihide Tanimoto .  Gallbladder microbiota composition is associated with pancreaticobiliary and gallbladder cancer prognosis. .  BMC microbiology22 ( 1 ) 147 - 147   2022.5Gallbladder microbiota composition is associated with pancreaticobiliary and gallbladder cancer prognosis.Reviewed International journal

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    BACKGROUND: The microbial population of the intestinal tract and its relationship to specific diseases has been extensively studied during the past decade. However, reports characterizing the bile microbiota are rare. This study aims to investigate the microbiota composition in patients with pancreaticobiliary cancers and benign diseases by 16S rRNA gene amplicon sequencing and to evaluate its potential value as a biomarker for the cancer of the bile duct, pancreas, and gallbladder. RESULTS: We enrolled patients who were diagnosed with cancer, cystic lesions, and inflammation of the pancreaticobiliary tract. The study cohort comprised 244 patients. We extracted microbiome-derived DNA from the bile juice in surgically resected gallbladders. The microbiome composition was not significantly different according to lesion position and cancer type in terms of alpha and beta diversity. We found a significant difference in the relative abundance of Campylobacter, Citrobacter, Leptotrichia, Enterobacter, Hungatella, Mycolicibacterium, Phyllobacterium and Sphingomonas between patients without and with lymph node metastasis. CONCLUSIONS: There was a significant association between the relative abundance of certain microbes and overall survival prognosis. These microbes showed association with good prognosis in cholangiocarcinoma, but with poor prognosis in pancreatic adenocarcinoma, and vice versa. Our findings suggest that pancreaticobiliary tract cancer patients have an altered microbiome composition, which might be a biomarker for distinguishing malignancy.

    DOI: 10.1186/s12866-022-02557-3

    PubMed

  • 比嘉 那優大, 赤羽 俊章, 横山 勢也, 米澤 大, 内田 裕之, 浜田 大治, 霧島 茉莉, 谷本 昭英, 花谷 亮典, 吉本 幸司 .  IDH wild-type GBMにおけるPDGFRA amplificationおよびMGMTpの予後への影響 .  Brain Tumor Pathology39 ( Suppl. ) 086 - 086   2022.5IDH wild-type GBMにおけるPDGFRA amplificationおよびMGMTpの予後への影響Reviewed

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    Language:Japanese   Publisher:日本脳腫瘍病理学会  

  • Taiji Hamada, Toshiaki Akahane, Seiya Yokoyama, Nayuta Higa, Mari Kirishima, Kei Matsuo, Michiko Shimokawa, Koji Yoshimoto, Akihide Tanimoto .  An oncogenic splice variant of PDGFRα in adult glioblastoma as a therapeutic target for selective CDK4/6 inhibitors. .  Scientific reports12 ( 1 ) 1275 - 1275   2022.1An oncogenic splice variant of PDGFRα in adult glioblastoma as a therapeutic target for selective CDK4/6 inhibitors.Reviewed International journal

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    Understanding human genome alterations is necessary to optimize genome-based cancer therapeutics. However, some newly discovered mutations remain as variants of unknown significance (VUS). Here, the mutation c.1403A > G in exon 10 of the platelet-derived growth factor receptor-alpha (PDGFRA) gene, a VUS found in adult glioblastoma multiforme (GBM), was introduced in human embryonal kidney 293 T (HEK293T) cells using genome editing to investigate its potential oncogenic functions. Genome editing was performed using CRISPR/Cas9; the proliferation, drug sensitivity, and carcinogenic potential of genome-edited cells were investigated. We also investigated the mechanism underlying the observed phenotypes. Three GBM patients carrying the c.1403A > G mutation were studied to validate the in vitro results. The c.1403A > G mutation led to a splice variant (p.K455_N468delinsN) because of the generation of a 3'-acceptor splice site in exon 10. PDGFRA-mutated HEK293T cells exhibited a higher proliferative activity via PDGFRα and the cyclin-dependent kinase (CDK)4/CDK6-cyclin D1 signaling pathway in a ligand-independent manner. They showed higher sensitivity to multi-kinase, receptor tyrosine kinase, and CDK4/CDK6 inhibitors. Of the three GBM patients studied, two harbored the p.K455_N468delinsN splice variant. The splicing mutation c.1403A > G in PDGFRA is oncogenic in nature. Kinase inhibitors targeting PDGFRα and CDK4/CDK6 signaling should be evaluated for treating GBM patients harboring this mutation.

    DOI: 10.1038/s41598-022-05391-9

    PubMed

  • Nayuta Higa, Toshiaki Akahane, Seiya Yokoyama, Hajime Yonezawa, Hiroyuki Uchida, Tomoko Takajo, Ryosuke Otsuji, Taiji Hamada, Kei Matsuo, Mari Kirishima, Nobuhiro Hata, Ryosuke Hanaya, Akihide Tanimoto, Koji Yoshimoto .  Prognostic impact of <i>PDGFRA</i> gain/amplification and <i>MGMT</i> promoter methylation status in patients with <i>IDH</i> wild-type glioblastoma .  Neuro-Oncology Advances4 ( 1 ) vdac097   2022.1Reviewed International journal

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Oxford University Press (OUP)  

    Abstract

    Background

    Platelet-derived growth factor receptor alpha (PDGFRA) is the second most frequently mutated tyrosine kinase receptor in glioblastoma (GBM). However, the prognostic impact of PDGFRA amplification on GBM patients remains unclear. Herein, we evaluated this impact by retrospectively analyzing outcomes of patients with IDH wild-type GBM.

    Methods

    Using a custom-made oncopanel, we evaluated PDGFRA gain/amplification in 107 GBM samples harboring wild-type IDH, along with MGMT promoter (MGMTp) methylation status.

    Results

    We detected PDGFRA gain/amplification in 31 samples (29.0%). PDGFRA gain/amplification predicted poor prognosis (P = .003). Compared to unamplified PDGFRA, PDGFRA gain/amplification in GBM was associated with higher patient age (P = .031), higher Ki-67 score (P = .019), and lower extent of surgical resection (P = .033). Unmethylated MGMTp also predicted poor prognosis (P = .005). As PDGFRA gain/amplification and unmethylated MGMTp were independent factors for poor prognosis in multivariate analyses, we grouped GBM cases based on PDGFRA and MGMTp status: poor (PDGFRA gain/amplification and unmethylated MGMTp), intermediate (PDGFRA gain/amplification or unmethylated MGMTp), and good (PDGFRA intact and methylated MGMTp) prognosis. The Kaplan-Meier survival analysis indicated that these groups significantly correlated with the OS of GBM patients (P &amp;lt; .001).

    Conclusions

    Here we report that PDGFRA gain/amplification is a predictor of poor prognosis in IDH wild-type GBM. Combining PDGFRA gain/amplification with MGMTp methylation status improves individual prognosis prediction in patients with IDH wild-type GBM.

    DOI: 10.1093/noajnl/vdac097

    PubMed

    Other Link: https://academic.oup.com/noa/article-pdf/4/1/vdac097/45178840/vdac097.pdf

  • Kodai Nakamura, Naomi Hiyake, Tomofumi Hamada, Seiya Yokoyama, Kazuki Mori, Kouta Yamashiro, Mahiro Beppu, Yasuaki Sagara, Yoshiaki Sagara, Tsuyoshi Sugiura .  Circulating microRNA Panel as a Potential Novel Biomarker for Oral Squamous Cell Carcinoma Diagnosis. .  Cancers13 ( 3 )   2021.1Circulating microRNA Panel as a Potential Novel Biomarker for Oral Squamous Cell Carcinoma Diagnosis.Reviewed International journal

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    A lack of reliable biomarkers for oral squamous cell carcinoma (OSCC) poses a major clinical issue. The sensitivity and specificity of classical serum tumor markers, such as the squamous cell carcinoma antigen (SCC-Ag), are quite poor, especially for early detection. This study aimed to identify specific serum miRNAs potentially serving as OSCC biomarkers. The expression levels of candidate miRNAs in serum samples from 40 OSCC patients and 40 healthy controls were quantitatively analyzed via microarray and reverse transcription PCR (RT-PCR) analyses. To enhance the accuracy of detection, we used Fisher's linear discriminant analysis to establish a diagnostic model that incorporated a combination of selected miRNAs. Consequently, miR-19a and miR-20a were significantly upregulated in the patient group (p = 0.014 and 0.036, respectively), whereas miR-5100 was downregulated (p = 0.001). We found that a combination of six miRNAs (miR-24, miR-20a, miR-122, miR-150, miR-4419a, and miR-5100) could distinguish between OSCC and the control group with a higher degree of accuracy (Area Under the Curve, AUC: 0.844, sensitivity: 55%, and specificity: 92.5%). Furthermore, compared to serum SCC antigen, the 6-miRNA panel could accurately detect the presence of OSCC. The present specific miRNAs panel may serve as a novel candidate biomarker of oral cancer.

    DOI: 10.3390/cancers13030449

    PubMed

  • Yusuke Kobayashi, Ikumi Kitazono, Toshiaki Akahane, Shintaro Yanazume, Masaki Kamio, Shinichi Togami, Sachio Nohara, Ippei Sakamoto, Seiya Yokoyama, Kazuhiro Tabata, Hiroaki Kobayashi, Akihide Tanimoto .  Molecular Evaluation of Endometrial Dedifferentiated Carcinoma, Endometrioid Carcinoma, Carcinosarcoma, and Serous Carcinoma Using a Custom-Made Small Cancer Panel. .  Pathology oncology research : POR27   1610013 - 1610013   2021Molecular Evaluation of Endometrial Dedifferentiated Carcinoma, Endometrioid Carcinoma, Carcinosarcoma, and Serous Carcinoma Using a Custom-Made Small Cancer Panel.Reviewed International journal

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    It is often difficult to histologically differentiate among endometrial dedifferentiated carcinoma (DC), endometrioid carcinoma (EC), serous carcinoma (SC), and carcinosarcoma (CS) due to the presence of solid components. In this study, we aimed to categorize these carcinomas according to The Cancer Genome Atlas (TCGA) classification using a small custom-made cancer genome panel (56 genes and 17 microsatellite regions) for integrated molecular diagnosis. A total of 36 endometrial cancer cases with solid components were assessed using IHC, next-generation sequencing (NGS), and the custom-made panel. Among 19 EC cases, six were categorized as MMR-deficient (MMR-d) and eight were classified as having a nonspecific molecular profile. Three EC cases were classified as POLE mutation (POLEmut)-type, which had a very high tumor mutation burden (TMB) and low microsatellite instability (MSI). Increased TMB and MSI were observed in all three DC cases, classified as MMR-d with mutations in MLH1 and POLD1. Except for one case classified as MMR-d, all SC cases exhibited TP53 mutations and were classified as p53 mutation-type. SC cases also exhibited amplification of CCND1, CCNE1, and MYC. CS cases were classified as three TCGA types other than the POLEmut-type. The IHC results for p53 and ARID1A were almost consistent with their mutation status. NGS analysis using a small panel enables categorization of endometrial cancers with solid proliferation according to TCGA classification. As TCGA molecular classification does not consider histological findings, an integrated analytical procedure including IHC and NGS may be a practical diagnostic tool for endometrial cancers.

    DOI: 10.3389/pore.2021.1610013

    PubMed

  • Nayuta Higa, Toshiaki Akahane, Seiya Yokoyama, Hajime Yonezawa, Hiroyuki Uchida, Tomoko Takajo, Mari Kirishima, Taiji Hamada, Kei Matsuo, Shingo Fujio, Tomoko Hanada, Hiroshi Hosoyama, Masanori Yonenaga, Akihisa Sakamoto, Tsubasa Hiraki, Akihide Tanimoto, Koji Yoshimoto .  A tailored next-generation sequencing panel identified distinct subtypes of wildtype IDH and TERT promoter glioblastomas. .  Cancer science111 ( 10 ) 3902 - 3911   2020.10A tailored next-generation sequencing panel identified distinct subtypes of wildtype IDH and TERT promoter glioblastomas.Reviewed International journal

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    Central nervous system tumors are classified based on an integrated diagnosis combining histology and molecular characteristics, including IDH1/2 and H3-K27M mutations, as well as 1p/19q codeletion. Here, we aimed to develop and assess the feasibility of a glioma-tailored 48-gene next-generation sequencing (NGS) panel for integrated glioma diagnosis. We designed a glioma-tailored 48-gene NGS panel for detecting 1p/19q codeletion and mutations in IDH1/2, TP53, PTEN, PDGFRA, NF1, RB1, CDKN2A/B, CDK4, and the TERT promoter (TERTp). We analyzed 106 glioma patients (grade II: 19 cases, grade III: 23 cases, grade IV: 64 cases) using this system. The 1p/19q codeletion was detected precisely in oligodendroglial tumors using our NGS panel. In a cohort of 64 grade Ⅳ gliomas, we identified 56 IDH-wildtype glioblastomas. Within these IDH-wildtype glioblastomas, 33 samples (58.9%) showed a mutation in TERTp. Notably, PDGFRA mutations and their amplification were more commonly seen in TERTp-wildtype glioblastomas (43%) than in TERTp-mutant glioblastomas (6%) (P = .001). Hierarchical molecular classification of IDH-wildtype glioblastomas revealed 3 distinct groups of IDH-wildtype glioblastomas. One major cluster was characterized by mutations in PDGFRA, amplification of CDK4 and PDGFRA, homozygous deletion of CDKN2A/B, and absence of TERTp mutations. This cluster was significantly associated with older age (P = .021), higher Ki-67 score (P = .007), poor prognosis (P = .012), and a periventricular tumor location. We report the development of a glioma-tailored NGS panel for detecting 1p/19q codeletion and driver gene mutations on a single platform. Our panel identified distinct subtypes of IDH- and TERTp-wildtype glioblastomas with frequent PDGFRA alterations.

    DOI: 10.1111/cas.14597

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  • Toshiaki Akahane, Ikumi Kitazono, Shintaro Yanazume, Masaki Kamio, Shinichi Togami, Ippei Sakamoto, Sachio Nohara, Seiya Yokoyama, Hiroaki Kobayashi, Tsubasa Hiraki, Shinsuke Suzuki, Shinichi Ueno, Akihide Tanimoto .  Next-generation sequencing analysis of endometrial screening liquid-based cytology specimens: a comparative study to tissue specimens. .  BMC medical genomics13 ( 1 ) 1 - 12   2020Next-generation sequencing analysis of endometrial screening liquid-based cytology specimens: a comparative study to tissue specimens.Reviewed International journal

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    BACKGROUND: Liquid-based cytology (LBC) is now a widely used method for cytologic screening and cancer diagnosis. Since the cells are fixed with alcohol-based fixatives, and the specimens are stored in a liquid condition, LBC specimens are suitable for genetic analyses. METHODS: Here, we established a small cancer gene panel, including 60 genes and 17 microsatellite markers for next-generation sequencing, and applied to residual LBC specimens obtained by endometrial cancer screening to compare with corresponding formalin-fixed paraffin-embedded (FFPE) tissues. RESULTS: A total of 49 FFPE and LBC specimens (n = 24) were analyzed, revealing characteristic mutations for endometrial cancer, including PTEN, CTNNB1, PIK3CA, and PIK3R1 mutations. Eight cases had higher scores for both tumor mutation burden (TMB) and microsatellite instability (MSI), which agree with defective mismatch repair (MMR) protein expression. Paired endometrial LBC, and biopsied and/or resected FFPE tissues from 7 cases, presented almost identical mutations, TMB, and MSI profiles in all cases. CONCLUSION: These findings demonstrate that our ad hoc cancer gene panel enabled the detection of therapeutically actionable gene mutations in endometrial LBC and FFPE specimens. Endometrial cancer LBC specimens offer an alternative and affordable source of molecular testing materials.

    DOI: 10.1186/s12920-020-00753-6

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  • Ikumi Kitazono, Taiji Hamada, Takuya Yoshimura, Mari Kirishima, Seiya Yokoyama, Toshiaki Akahane, Akihide Tanimoto .  PCP4/PEP19 downregulates neurite outgrowth via transcriptional regulation of Ascl1 and NeuroD1 expression in human neuroblastoma M17 cells. .  Laboratory investigation; a journal of technical methods and pathology100 ( 12 ) 1551 - 1563   2020PCP4/PEP19 downregulates neurite outgrowth via transcriptional regulation of Ascl1 and NeuroD1 expression in human neuroblastoma M17 cells.Reviewed International journal

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    Purkinje cell protein 4/peptide 19 (PCP4/PEP19) is 7.6 kDa peptide originally found in Purkinje cells. PCP4/PEP19 is a differentiation maker of Purkinje cells, where it functions as an antiapoptotic factor. Cerebral neuronal cells also express PCP4/PEP19, which may be related to neuronal cell survival. However, evidence suggests that PCP4/PEP19 may also be involved in neuronal differentiation. Here, we investigated the effects of PCP4/PEP19 expression on neuronal differentiation by analyzing neurite outgrowth, and expression of neuronal differentiation markers in cultured human neuroblastoma M17 cells. When PCP4/PEP19 expression was reduced by siRNA-mediated knockdown, neurite outgrowth was significantly increased. Among many differentiation markers tested, expression of NeuroD1 was increased, while that of Ascl1 was decreased upon PCP4/PEP19 knockdown. Furthermore, luciferase reporter assays revealed that PCP4/PEP19 knockdown upregulated NeuroD1 and downregulated Ascl1 expression, at the transcriptional level. These results suggest a new function of PCP4/PEP19, which suppresses neurite outgrowth and neuronal differentiation through the regulation of NeuroD1 and Ascl1 expression in M17 cells. Furthermore, immunohistochemical studies showed that PCP4/PEP19 localizes in the nuclei of human neuroblastoma cells. Therefore, PCP4/PEP19 may also be an intranuclear negative regulator of neuronal differentiation and may thus be a potential therapeutic target to promote cellular differentiation in human neuroblastoma.

    DOI: 10.1038/s41374-020-0462-z

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  • Seiya Yokoyama, Taiji Hamada, Michiyo Higashi, Kei Matsuo, Kosei Maemura, Hiroshi Kurahara, Michiko Horinouchi, Tsubasa Hiraki, Tomoyuki Sugimoto, Toshiaki Akahane, Suguru Yonezawa, Marko Kornmann, Surinder K Batra, Michael A Hollingsworth, Akihide Tanimoto .  Predicted Prognosis of Patients with Pancreatic Cancer by Machine Learning. .  Clinical cancer research : an official journal of the American Association for Cancer Research26 ( 10 ) 2411 - 2421   2020Reviewed International journal

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    PURPOSE: Pancreatic cancer remains a disease of high mortality despite advanced diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic cancers. MUC1 and MUC4 expression are related to the aggressive behavior of human neoplasms and a poor patient outcome. In contrast, MUC2 is a tumor suppressor, and we have previously reported that MUC2 is a favorable prognostic factor in pancreatic neoplasia. This study investigates whether the methylation status of three mucin genes from postoperative tissue specimens from patients with pancreatic neoplasms could serve as a predictive biomarker for outcome after surgery. EXPERIMENTAL DESIGN: We evaluated the methylation status of MUC1, MUC2, and MUC4 promoter regions in pancreatic tissue samples from 191 patients with various pancreatic lesions using methylation-specific electrophoresis. Then, integrating these results and clinicopathologic features, we used support vector machine-, neural network-, and multinomial-based methods to develop a prognostic classifier. RESULTS: Significant differences were identified between the positive- and negative-prediction classifiers of patients in 5-year overall survival (OS) in the cross-validation test. Multivariate analysis revealed that these prognostic classifiers were independent prognostic factors analyzed by not only neoplastic tissues but also nonneoplastic tissues. These classifiers had higher predictive accuracy for OS than tumor size, lymph node metastasis, distant metastasis, and age and can complement the prognostic value of the TNM staging system. CONCLUSIONS: Analysis of epigenetic changes in mucin genes may be of diagnostic utility and one of the prognostic predictors for patients with pancreatic ductal adenocarcinoma.

    DOI: 10.1158/1078-0432.CCR-19-1247

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  • Xin Guo, Hirotsugu Noguchi, Naoki Ishii, Takujiro Homma, Taiji Hamada, Tsubasa Hiraki, Jing Zhang, Kei Matsuo, Seiya Yokoyama, Hiroaki Ishibashi, Tomoko Fukushige, Takuro Kanekura, Junichi Fujii, Hidetaka Uramoto, Akihide Tanimoto, Sohsuke Yamada .  The Association of Peroxiredoxin 4 with the Initiation and Progression of Hepatocellular Carcinoma. .  Antioxidants & redox signaling30 ( 10 ) 1271 - 1284   2019.4The Association of Peroxiredoxin 4 with the Initiation and Progression of Hepatocellular Carcinoma.Reviewed International journal

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    AIMS: Peroxiredoxin 4 (PRDX4) is a member of the peroxiredoxin family of antioxidant enzymes. Previously, we reported that PRDX4 can restrain the initiation and progression of nonalcoholic steatohepatitis by reducing local and systemic reactive oxygen species (ROS) levels. Oxidative stress is recognized as a key factor in hepatocarcinogenesis, and a high ROS level has also been found in hepatocellular carcinoma (HCC). Here, our aim is to investigate roles of PRDX4 in the initiation and progression of HCC. RESULTS: In this study, for hepatocarcinogenesis, wild-type (WT), PRDX4 knockout (PRDX4-/y), and human PRDX4 transgenic (hPRDX4+/+) mice were given a weekly intraperitoneal injection of diethylnitrosamine for 25 weeks. The HCC incidence was higher in PRDX4-/y mice than in WT or hPRDX4+/+ mice. Intrahepatic and circulating oxidative stress and inflammatory cell infiltration in the liver were obviously decreased in hPRDX4+/+ mice, compared with WT mice. Furthermore, in our cohort study, human HCC specimens with low expression of PRDX4 had higher ROS levels and a highly malignant phenotype, which was associated with a reduced overall survival, compared with those with high PRDX4 expression. However, in human HCC cell lines, PRDX4 knockdown led to a rapidly increased intracellular ROS level and suppressed cell proliferation, inducing cell death. Innovation and Conclusion: Our results clearly indicate that PRDX4 has an inhibitory effect in the initiation of HCC, but a dual (inhibitory or promoting) role in the progression of HCC, suggesting the potential utility of PRDX4 activators or inhibitors as therapy for different stages and phenotypes of HCC.

    DOI: 10.1089/ars.2017.7426

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  • Jing Zhang, Xin Guo, Taiji Hamada, Seiya Yokoyama, Yuka Nakamura, Jianbo Zheng, Nozomu Kurose, Yasuhito Ishigaki, Hidetaka Uramoto, Akihide Tanimoto, Sohsuke Yamada .  Protective Effects of Peroxiredoxin 4 (PRDX4) on Cholestatic Liver Injury. .  International journal of molecular sciences19 ( 9 )   2018.8Protective Effects of Peroxiredoxin 4 (PRDX4) on Cholestatic Liver Injury.Reviewed International journal

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    Accumulating evidence indicates that oxidative stress plays a critical role in initiating the progression of inflammatory and fibrotic liver diseases, including cholestatic hepatitis. Peroxiredoxin 4 (PRDX4) is a secretory antioxidase that protects against oxidative damage by scavenging reactive oxygen species (ROS) in both the intracellular compartments and extracellular space. In this study, we examined the in vivo net effects of PRDX4 overexpression in a murine model of cholestasis. To induce cholestatic liver injury, we subjected C57BL/6J wild-type (WT) or human PRDX4 (hPRDX4) transgenic (Tg) mice to sham or bile duct ligation (BDL) surgery for seven days. Our results showed that the liver necrosis area was significantly suppressed in Tg BDL mice with a reduction in the severity of liver injuries. Furthermore, PRDX4 overexpression markedly reduced local and systemic oxidative stress generated by BDL. In addition, suppression of inflammatory cell infiltration, reduced proliferation of hepatocytes and intrahepatic bile ducts, and less fibrosis were also found in the liver of Tg BDL mice, along with a reduced mortality rate after BDL surgery. Interestingly, the composition of the hepatic bile acids (BAs) was more beneficial for Tg BDL mice than for WT BDL mice, suggesting that PRDX4 overexpression may affect BA metabolism during cholestasis. These features indicate that PRDX4 plays an important role in protecting against liver injury following BDL and might be a promising therapeutic modality for cholestatic diseases.

    DOI: 10.3390/ijms19092509

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  • Kie Honjo, Taiji Hamada, Takuya Yoshimura, Seiya Yokoyama, Sohsuke Yamada, Yan-Qin Tan, Lai K Leung, Norifumi Nakamura, Yasuyo Ohi, Michiyo Higashi, Akihide Tanimoto .  PCP4/PEP19 upregulates aromatase gene expression via CYP19A1 promoter I.1 in human breast cancer SK-BR-3 cells. .  Oncotarget9 ( 51 ) 29619 - 29633   2018.7PCP4/PEP19 upregulates aromatase gene expression via CYP19A1 promoter I.1 in human breast cancer SK-BR-3 cells.Reviewed International journal

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    The Purkinje cell protein 4/peptide 19 (PCP4/PEP19) is a novel breast cancer cell expressing peptide, originally found in the neural cells as an anti-apoptotic factor, could inhibit cell apoptosis and enhance cell migration and invasion in human breast cancer cell lines. The expression of PCP4/PEP19 is induced by estrogens in estrogen receptor-positive (ER+) MCF-7 cells but also highly expressed in ER- SK-BR-3 cells. In this study, we investigated the effects of PCP4/PEP19 on aromatase gene expression in MCF-7 and SK-BR-3 human breast cancer cells. In SK-BR-3 cells but not in MCF-7 cells, PCP4/PEP19 knockdown by siRNA silencing decreased the aromatase expression in gene transcriptional level. When PCP4/PEP19 was overexpressed by CMV promoter-driven PCP4/PEP19 expressing plasmid transfection, aromatase gene transcription increased in SK-BR-3 cells. This aromatase gene transcription is mainly mediated through promoter region PI.1, which is usually active in the placental tissue but not in the breast cancer tissue. These results indicate a new function of PCP4/PEP19 that would enhance aromatase gene upregulation to supply estrogens in heterogeneous cancer microenvironment.

    DOI: 10.18632/oncotarget.25651

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  • 横山 勢也, 東 美智代, 谷本 昭英, 米澤 傑 .  【肝胆膵疾患のエピジェネティクスを学ぶ】 膵疾患のエピジェネティクス 膵癌におけるメチル化によるムチン発現調節 .  肝・胆・膵76 ( 5 ) 945 - 950   2018.5【肝胆膵疾患のエピジェネティクスを学ぶ】 膵疾患のエピジェネティクス 膵癌におけるメチル化によるムチン発現調節

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  • The Association of Peroxiredoxin 4 with the Initiation and Progression of Hepatocellular Carcinoma. .  Antioxidants & Redox Signaling   2018.4The Association of Peroxiredoxin 4 with the Initiation and Progression of Hepatocellular Carcinoma.Reviewed

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    DOI: doi.org/10.1089/ars.2017.7426

  • Atsushi Matsuda, Michiyo Higashi, Tomomi Nakagawa, Seiya Yokoyama, Atsushi Kuno, Suguru Yonezawa, Hisashi Narimatsu .  Assessment of tumor characteristics based on glycoform analysis of membrane-tethered MUC1 (vol 97, pg 1103, 2017) .  LABORATORY INVESTIGATION97 ( 10 ) 1262 - 1262   2017.10Assessment of tumor characteristics based on glycoform analysis of membrane-tethered MUC1 (vol 97, pg 1103, 2017)Reviewed

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    DOI: 10.1038/labinvest.2017.67

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  • Seiya Yokoyama, Michiyo Higashi, Hideaki Tsutsumida, Jouji Wakimoto, Tomofumi Hamada, Edwin Wiest, Kei Matsuo, Ikumi Kitazono, Yuko Goto, Xin Guo, Taiji Hamada, Sohsuke Yamada, Tsubasa Hiraki, Suguru Yonezawa, Surinder K Batra, Michael A Hollingsworth, Akihide Tanimoto .  TET1-mediated DNA hypomethylation regulates the expression of MUC4 in lung cancer. .  Genes & cancer8 ( 3-4 ) 517 - 527   2017TET1-mediated DNA hypomethylation regulates the expression of MUC4 in lung cancer.Reviewed International journal

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    Lung cancer remains a disease of high mortality, despite advanced diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in lung neoplasms. Our immunohistochemistry (IHC) studies have shown that high MUC4 expression correlates with a poor outcome. We have also shown that the expression of several mucin genes in cancer cell lines is regulated by DNA methylation. We evaluated the expression level of MUC4, mRNA and several DNA hypomethylation factors in lung tissue samples from 33 patients with various lung lesions. The results indicated that the DNA methylation status of MUC4 matched the expression level of mRNA. In addition, the TET1 (Ten-Eleven Translocation) mRNA showed a significant correlation with the status of DNA methylation of MUC4. Furthermore, the treatment of a lung cancer cell line with TET1 siRNA caused a reduction in MUC4 mRNA expression. Thus, we suggest that TET1 mediated DNA hypomethylation plays a key role in the expression of MUC4. This is the first report that TET1 mediated DNA hypomethylation regulates the expression of MUC4 in lung cancer. The analysis of these epigenetic changes may be useful for diagnosing carcinogenic risk.

    DOI: 10.18632/genesandcancer.139.

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  • Atsushi Matsuda, Michiyo Higashi, Tomomi Nakagawa, Seiya Yokoyama, Atsushi Kuno, Suguru Yonezawa, Hisashi Narimatsu .  Assessment of tumor characteristics based on glycoform analysis of membrane-tethered MUC1 .  Laboratory Investigation97 ( 9 ) 1103 - 1113   2017Assessment of tumor characteristics based on glycoform analysis of membrane-tethered MUC1Reviewed

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:Nature Publishing Group  

    Clinical tissue specimens are useful for pathological diagnosis, which is, in some cases, supported by visualization of biomolecule localization. In general, diagnostic specificity in molecular pathology is increased by the acquisition of a probe to distinguish the modification of isomers. Although glycosylation is one of the candidate modifications in a protein, comparative glycan analysis of disease-associated proteins derived from a single tissue section is still challenging because of the lack of analytical sensitivity. Here we demonstrate a possible method for differential glycoform analysis of an endogenous tumor-associated glycoprotein MUC1 by an antibody-overlay lectin microarray. Tissue sections (5 μm thick) of patients with cholangiocarcinoma (CCA
    n=21) and pancreatic ductal adenocarcinoma (PDAC
    n=50) were stained with an anti-MUC1 antibody MY.1E12 that was established as a monoclonal antibody recognizing an MUC1 glycosylation isoform with a sialyl-core 1 structure (NeuAcα2-3galactosyl β1-3-N-acetylgalactosamine). MY.1E12-positive tissue areas (2.5 mm 2) were selectively dissected with a laser capture microdissection procedure. The membrane MUC1 was enriched by immunoprecipitation with MY.1E12 and subjected to lectin microarray analysis. Even though the reactivities of MY.1E12 between CCA and PDAC were similar, the lectin-binding patterns varied. We found Maackia amurensis leukoagglutinin and pokeweed lectin distinguished MY.1E12-reactive MUC1 of CCA from that of PDAC. Moreover, MUC1 with M. amurensis hemagglutinin (MAH) reactivity potentially reflected the degree of malignancy. These results were confirmed with MAH-MY.1E12 double fluorescent immunostaining. These glycan changes on MUC1 were detected with high sensitivity owing to the cluster effect of immobilized lectins on a tandem repeat peptide antigen covered with highly dense glycosylation such as mucin. Our approach provides the information to investigate novel glycodynamics in biology, for example, glycoalteration, as well as diseases related to not only MUC1 but also other membrane proteins.

    DOI: 10.1038/labinvest.2017.53

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  • Tsubasa Hiraki, Sohsuke Yamada, Michiyo Higashi, Kazuhito Hatanaka, Seiya Yokoyama, Ikumi Kitazono, Yuko Goto, Mari Kirishima, Surinder K. Batra, Suguru Yonezawa, Akihide Tanimoto .  Immunohistochemical expression of mucin antigens in gallbladder adenocarcinoma: MUC1-positive and MUC2-negative expression is associated with vessel invasion and shortened survival .  HISTOLOGY AND HISTOPATHOLOGY32 ( 6 ) 585 - 596   2016.9Immunohistochemical expression of mucin antigens in gallbladder adenocarcinoma: MUC1-positive and MUC2-negative expression is associated with vessel invasion and shortened survivalReviewed

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    Mucins play pivotal roles in influencing cancer biology, for example affecting carcinoma invasion, aggressiveness and/or metastatic potential. Our aim is to investigate the significance of expression profiles of two mucins in particular, MUC1 and MUC2, their correlations with various clinicopathological features, and prognosis in gallbladder adenocarcinoma (GBAC). We performed immunohistochemistry from patients with surgically resected GBAC, using antibodies against mucin core proteins MUC1/DF3 and MUC2/Ccp58 in 81 paraffin-embedded tumor samples. MUC1 or MUC2 expression was considered to be high when &gt;= 20% or 10% of the GBAC cells showed positive staining, respectively. High MUC1 expression was revealed to have a significant relationship to the presence of pathologically lymphatic and vascular invasion, and regional lymph node metastasis. By contrast, high MUC2 expression showed a significant correlation with pathologically perineural invasion, T stage &gt;= 3, and post-operative recurrence. Moreover, MUC1 showed significantly positive co-expression and potentially complementary correlations with MUC2. Multivariate analyses demonstrated that the high MUC1 expression group had significantly shorter disease-specific survival times. However, the combination of both high MUC1 and MUC2 expression did not predict worse outcome in GBACs. Therefore, although each mucin has a somewhat important role in the pathogenesis of GBAC progression, MUC1 can independently predict vessel invasion and poor prognosis in patients with GBAC. The detection of MUC1 might well offer a useful parameter for providing clinical management and treatment against postsurgical GBACs.

    DOI: 10.14670/HH-11-824

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  • Seiya Yokoyama, Michiyo Higashi, Sho Kitamoto, Monika Oeldorf, Uwe Knippschild, Marko Kornmann, Kosei Maemura, Hiroshi Kurahara, Edwin Wiest, Tomofumi Hamada, Ikumi Kitazono, Yuko Goto, Takashi Tasaki, Tsubasa Hiraki, Kazuhito Hatanaka, Yuko Mataki, Hiroki Taguchi, Shinichi Hashimoto, Surinder K. Batra, Akihide Tanimoto, Suguru Yonezawa, Michael A. Hollingsworth .  Aberrant methylation of MUC1 and MUC4 promoters are potential prognostic biomarkers for pancreatic ductal adenocarcinomas .  ONCOTARGET7 ( 27 ) 42553 - 42565   2016.6Aberrant methylation of MUC1 and MUC4 promoters are potential prognostic biomarkers for pancreatic ductal adenocarcinomasReviewed

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:IMPACT JOURNALS LLC  

    Pancreatic cancer is still a disease of high mortality despite availability of diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic neoplasms. MUC1 and MUC4 are high molecular weight transmembrane mucins. These are overexpressed in many carcinomas, and high expression of these molecules is a risk factor associated with poor prognosis. We evaluated the methylation status of MUC1 and MUC4 promoter regions in pancreatic tissue samples from 169 patients with various pancreatic lesions by the methylation specific electrophoresis (MSE) method. These results were compared with expression of MUC1 and MUC4, several DNA methylation/demethylation factors (e.g. ten-eleven translocation or TET, and activation-induced cytidine deaminase or AID) and CAIX (carbonic anhydrase IX, as a hypoxia biomarker). These results were also analyzed with clinicopathological features including time of overall survival of PDAC patients. We show that the DNA methylation status of the promoters of MUC1 and MUC4 in pancreatic tissue correlates with the expression of MUC1 and MUC4 mRNA. In addition, the expression of several DNA methylation/demethylation factors show a significant correlation with MUC1 and MUC4 methylation status. Furthermore, CAIX expression significantly correlates with the expression of MUC1 and MUC4. Interestingly, our results indicate that low methylation of MUC1 and/or MUC4 promoters correlates with decreased overall survival. This is the first report to show a relationship between MUC1 and/or MUC4 methylation status and prognosis. Analysis of epigenetic changes in mucin genes may be of diagnostic utility and one of the prognostic predictors for patients with PDAC.

    DOI: 10.18632/oncotarget.9924

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    Other Link: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=9924&pubmed-linkout=1

  • Michiyo Higashi, Seiya Yokoyama, Takafumi Yamamoto, Yuko Goto, Ikumi Kitazono, Tsubasa Hiraki, Hiroki Taguchi, Shinichi Hashimoto, Yoshihiko Fukukura, Chihaya Koriyama, Yuko Mataki, Kosei Maemura, Hiroyuki Shinchi, Maneesh Jain, Surinder K. Batra, Suguru Yonezawa .  Mucin Expression in Endoscopic Ultrasound-Guided Fine-Needle Aspiration Specimens Is a Useful Prognostic Factor in Pancreatic Ductal Adenocarcinoma .  PANCREAS44 ( 5 ) 728 - 734   2015.7Mucin Expression in Endoscopic Ultrasound-Guided Fine-Needle Aspiration Specimens Is a Useful Prognostic Factor in Pancreatic Ductal AdenocarcinomaReviewed

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:LIPPINCOTT WILLIAMS & WILKINS  

    Objectives The aim of this study was to further examine the utility of mucin (MUC) expression profiles as prognostic factors in pancreatic ductal adenocarcinoma (PDAC).
    Methods Mucin expression was examined by immunohistochemistry analysis in endoscopic ultrasound-guided fine-needle aspiration specimens obtained from 114 patients with PDAC. The rate of expression of each MUC was compared with clinicopathologic features.
    Results The expression rates of MUCs in cancer lesions were MUC1, 87.7%; MUC2, 0.8%; MUC4, 93.0%; MUC5AC, 78.9%; MUC6, 24.6%; and MUC16, 67.5%. MUC1 and MUC4 were positive, and MUC2 was negative in most PDACs. Patients with advanced stage of PDAC with MUC5AC expression had a significantly better outcome than those who were MUC5AC-negative (P = 0.002). With increasing clinical stage, total MUC6 expression decreased (P for trend = 0.001) and MUC16 cytoplasmic expression increased (P for trend = 0.02). The prognosis of patients with MUC16 cytoplasmic expression was significantly poorer than those without this expression. Multivariate survival analysis revealed that MUC16 cytoplasmic expression was a significant independent predictor of a poor prognosis after adjusting for the effects of other prognostic factors (P = 0.002).
    Conclusions Mucin expression profiles in ultrasound-guided fine-needle aspiration specimens have excellent diagnostic utility and are useful predictors of outcome in patients with PDAC.

    DOI: 10.1097/MPA.0000000000000362

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    Other Link: http://journals.lww.com/pancreasjournal/Abstract/2015/07000/Mucin_Expression_in_Endoscopic_Ultrasound_Guided.6.aspx

  • Tsubasa Hiraki, Makoto Yoshimitsu, Tadaki Suzuki, Yuko Goto, Michiyo Higashi, Seiya Yokoyama, Tomohisa Tabuchi, Takahiro Futatsuki, Kentaro Nakamura, Hideki Hasegawa, Masayuki Saijo, Yasuyuki Kakihana, Naomichi Arima, Suguru Yonezawa .  Two autopsy cases of severe fever with thrombocytopenia syndrome (SFTS) in Japan: A pathognomonic histological feature and unique complication of SFTS .  PATHOLOGY INTERNATIONAL64 ( 11 ) 569 - 75   2014.11Two autopsy cases of severe fever with thrombocytopenia syndrome (SFTS) in Japan: A pathognomonic histological feature and unique complication of SFTSReviewed

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:WILEY-BLACKWELL  

    We report two autopsy cases of severe fever with thrombocytopenia syndrome (SFTS) with a high fatality rate in aged Japanese patients. Both cases were caused by a tick-bite. The pathognomonic histological feature was necrotizing lymphadenitis of systemic lymphoid tissue with SFTS viruses and SFTSV-RNA copies. Marked fungal infections were also observed in the lungs of both patients. Since cellular immune function may be suppressed in SFTS patients, physicians should be aware of possible fungal infections.

    DOI: 10.1111/pin.12207

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  • Tsubasa Hiraki, Michiyo Higashi, Yuko Goto, Ikumi Kitazono, Seiya Yokoyama, Hiroyuki Iuchi, Hiromi Nagano, Akihide Tanimoto, Suguru Yonezawa .  A rare case of internal jugular vein aneurysm with massive hemorrhage in neurofibromatosis type 1 .  CARDIOVASCULAR PATHOLOGY23 ( 4 ) 244 - 7   2014.7A rare case of internal jugular vein aneurysm with massive hemorrhage in neurofibromatosis type 1Reviewed

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:ELSEVIER SCIENCE INC  

    Neurofibromatosis Type 1 (NF1) is a relatively common autosomal dominant disorder. Vascular involvement is a well-recognized manifestation of NF1, but venous aneurysm associated with NF1 is extremely rare. We present a case of an NF1 patient with a left internal jugular vein aneurysm with massive hemorrhage occurring during surgery. Due to the extreme fragility of both the aneurismal wall and the surrounding tissue, the patient developed severe intraoperative bleeding. Pathological examination confirmed aneurismal wall infiltration of the neurofibromatosis. Physicians should be aware that hemorrhagic complication in NF1 can occur and be fatal. (C) 2014 The Authors. Published by Elsevier Inc.

    DOI: 10.1016/j.carpath.2014.02.001

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  • Yokoyama S, Kitamoto S, Higashi M, Goto Y, Hara T, Ikebe D, Yamaguchi T, Arisaka Y, Niihara T, Nishimata H, Tanaka S, Takaori K, Batra SK, Yonezawa S. .  Diagnosis of pancreatic neoplasms using a novel method of DNA methylation analysis of mucin expression in pancreatic juice. .  PLoS One9 ( 4 ) e93760 - doi: 10.1371/journal.pone.0093760   2014.4Diagnosis of pancreatic neoplasms using a novel method of DNA methylation analysis of mucin expression in pancreatic juice.Reviewed

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  • Shibahara H, Higashi M, Koriyama C, Yokoyama S, Kitazono I, Kurumiya Y, Narita M, Kuze S, Kyokane T, Mita S, Arai T, Kato T, Yuasa N, Yamaguchi R, Kubota H, Suzuki H, Baba S, Rousseau K, Batra SK, Yonezawa S. .  Pathobiological Implications of Mucin (MUC) Expression in the Outcome of Small Bowel Cancer. .  PLoS One9 ( 4 ) e86111 - doi: 10.1371/journal.pone.0086111.   2014.4Pathobiological Implications of Mucin (MUC) Expression in the Outcome of Small Bowel Cancer.Reviewed

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  • Hiraki T, Higashi M, Goto Y, Kitazono I, Yokoyama S, Iuchi H, Nagano H, Tanimoto A, Yonezawa S. .  A rare case of internal jugular vein aneurysm with massive hemorrhage in neurofibromatosis type 1. .  Cardiovasc Pathol.published online. ( doi: 10.1016/j.carpath.2014.02.001. )   2014A rare case of internal jugular vein aneurysm with massive hemorrhage in neurofibromatosis type 1.Reviewed

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  • Hiroaki Shibahara, Michiyo Higashi, Seiya Yokoyama, Karine Rousseau, Iwao Kitazono, Masahiko Osako, Hiroshi Shirahama, Yukie Tashiro, Yasuhiro Kurumiya, Michihiko Narita, Shingo Kuze, Hiroshi Hasagawa, Takehito Kato, Hitoshi Kubota, Hideaki Suzuki, Toshiyuki Arai, Yu Sakai, Norihiro Yuasa, Masahiko Fujino, Shinji Kondo, Yoshichika Okamoto, Tatsuyoshi Yamamoto, Takashi Hiromatsu, Eiji Sasaki, Kazuhisa Shirai, Satoru Kawai, Koutarou Hattori, Hideki Tsuji, Osamu Okochi, Masaki Sakamoto, Akinobu Kondo, Naomi Konishi, Surinder K. Batra, Suguru Yonezawa .  A Comprehensive Expression Analysis of Mucins in Appendiceal Carcinoma in a Multicenter Study: MUC3 Is a Novel Prognostic Factor .  PLOS ONE9 ( 12 ) e115613   2014A Comprehensive Expression Analysis of Mucins in Appendiceal Carcinoma in a Multicenter Study: MUC3 Is a Novel Prognostic FactorReviewed

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    Background: Mucins are implicated in survival in various cancers, but there have been no report addressed on survival in appendiceal carcinoma, an uncommon disease with different clinical and pathological features from those of other colon cancers. We aimed to investigate the clinical implications of expression of mucins in appendiceal carcinoma.
    Methods: Expression profiles of MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC6, MUC16 and MUC17 in cancer tissue were examined by immunohistochemistry in 108 cases of surgically resected appendiceal carcinoma.
    Results: The following relationships of mucins with clinicopathologic factors were identified: MUC1 with positive lymphatic invasion (p=0.036); MUC2 with histological type (mucinous carcinoma, p&lt;0.001), superficial invasion depth (p=0.007), negative venous invasion (p=0.003), and curative resection (p=0.019); MUC3 with non-curative resection (p=0.017); MUC5AC with histological type (mucinous carcinoma, p=0.002), negative lymphatic invasion (p=0.021), and negative venous invasion (p=0.022); and MUC16 with positive lymph node metastasis (p=0.035), positive venous invasion (p&lt;0.05), and non-curative resection (p=0.035). A poor prognosis was related to positive lymph node metastasis (p=0.04), positive lymphatic invasion (p=0.02), positive venous invasion (p&lt;0.001), non-curative resection (p&lt;0.001), and positive expression of MUC3 (p=0.004). In multivariate analysis, positive venous invasion (HR: 6.93, 95% CI: 1.93-24.96, p=0.003), non-curative resection (HR: 10.19, 95% CI: 3.05-34.07, p&lt;0.001) and positive MUC3 expression (HR: 3.37, 95% CI: 1.13-10.03, p=0.03) were identified as significant independent prognostic factors in patients with appendiceal carcinoma.
    Conclusions: Expression of MUC3 in appendiceal carcinoma is an independent factor for poor prognosis and a useful predictor of outcome in patients with appendiceal carcinoma after surgery.

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  • Hiroaki Shibahara, Michiyo Higashi, Chihaya Koriyama, Seiya Yokoyama, Iwao Kitazono, Yasuhiro Kurumiya, Michihiko Narita, Shingo Kuze, Takanori Kyokane, Saburo Mita, Toshiyuki Arai, Takehito Kato, Norihiro Yuasa, Ryuzo Yamaguchi, Hitoshi Kubota, Hideaki Suzuki, Satoshi Baba, Karine Rousseau, Surinder K. Batra, Suguru Yonezawa .  Pathobiological Implications of Mucin (MUC) Expression in the Outcome of Small Bowel Cancer .  PLOS ONE9 ( 4 ) e86111   2014Pathobiological Implications of Mucin (MUC) Expression in the Outcome of Small Bowel CancerReviewed

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    Mucins have been associated with survival in various cancer patients, but there have been no studies of mucins in small bowel carcinoma (SBC). In this study, we investigated the relationships between mucin expression and clinicopathologic factors in 60 SBC cases, in which expression profiles of MUC1, MUC2, MUC3, MUC4, MUC5AC, MUC6 and MUC16 in cancer and normal tissues were examined by immunohistochemistry. MUC1, MUC5AC and MUC16 expression was increased in SBC lesions compared to the normal epithelium, and expression of these mucins was related to clinicopathologic factors, as follows: MUC1 [tumor location (p = 0.019), depth (p = 0.017) and curability (p = 0.007)], MUC5AC [tumor location (p = 0.063) and lymph node metastasis (p = 0.059)], and MUC16 [venous invasion (p = 0.016) and curability (p = 0.016)]. Analysis of 58 cases with survival data revealed five factors associated with a poor prognosis: poorly-differentiated or neuroendocrine histological type (p&lt;0.001), lymph node metastasis (p&lt;0.001), lymphatic invasion (p = 0.026), venous invasion (p&lt;0.001) and curative resection (p&lt;0.001), in addition to expression of MUC1 (p = 0.042), MUC5AC (p = 0.007) and MUC16 (p&lt;0.001). In subsequent multivariate analysis with curability as the covariate, lymph node metastasis, venous invasion, and MUC5AC and/or MUC16 expression were significantly related to the prognosis. Multivariate analysis in curative cases (n = 45) showed that SBC with MUC5AC and/or MUC16 expression had a significantly independent high hazard risk after adjusting for the effects of venous invasion (hazard ratio: 5.6, 95% confidence interval: 1.8-17). In conclusion, the study shows that a MUC5AC-positive and/or MUC16-positive status is useful as a predictor of a poor outcome in patients with SBC.

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  • Seiya Yokoyama, Sho Kitamoto, Michiyo Higashi, Yuko Goto, Taro Hara, Dai Ikebe, Taketo Yamaguchi, Yoshifumi Arisaka, Toru Niihara, Hiroto Nishimata, Sadao Tanaka, Kyoichi Takaori, Surinder K. Batra, Suguru Yonezawa .  Diagnosis of Pancreatic Neoplasms Using a Novel Method of DNA Methylation Analysis of Mucin Expression in Pancreatic Juice .  PLOS ONE9 ( 4 ) e93760   2014Diagnosis of Pancreatic Neoplasms Using a Novel Method of DNA Methylation Analysis of Mucin Expression in Pancreatic JuiceReviewed

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    Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasms (IPMNs). Our immunohistochemistry (IHC) studies have shown a consensus position on mucin expression profiles in pancreatic neoplasms as follows: MUC1-positive but MUC2-negative expression in PDACs; MUC1-negative but MUC2-positive expression in intestinal-type IPMNs (dangerous type); MUC1-negative and MUC2-negative expression in gastric-type IPMNs (safe type); High MUC4 expression in PDAC patients with a poor outcome; and MUC4-positive expression in intestinal-type IPMNs. We also showed that three mucin genes (MUC1, MUC2 and MUC4) expression in cancer cell line was regulated by DNA methylation. We have developed a novel ' methylation-specific electrophoresis (MSE)' method to analyze the DNA methylation status of mucin genes by high sensitivity and resolution. By using the MSE method, we evaluated pancreatic juice samples from 45 patients with various pancreatic lesions. The results were compared with final diagnosis of the pancreatic lesions including IHC of mucin expression in the paired pancreatic tissues. The results indicated that the DNA methylation status of MUC1, MUC2 and MUC4 in pancreatic juice matched with the mucin expression in tissue. Analyses of the DNA methylation status of MUC1, MUC2 and MUC4 were useful for differential diagnosis of human pancreatic neoplasms, with specificity and sensitivity of 87% and 80% for PDAC; 100% and 88% for intestinal-type IPMN; and 88% and 77% for gastric-type IPMN, respectively. In conclusion, MSE analysis of human pancreatic juice may provide useful information for selection of treatment for pancreatic neoplasms.

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  • Iwao Kitazono, Michiyo Higashi, Sho Kitamoto, Seiya Yokoyama, Michiko Horinouchi, Masahiko Osako, Takeshi Shimizu, Mineo Tabata, Surinder K. Batra, Masamichi Goto, Suguru Yonezawa .  Expression of MUC4 Mucin Is Observed Mainly in the Intestinal Type of Intraductal Papillary Mucinous Neoplasm of the Pancreas .  PANCREAS42 ( 7 ) 1120 - 8   2013.10Expression of MUC4 Mucin Is Observed Mainly in the Intestinal Type of Intraductal Papillary Mucinous Neoplasm of the PancreasReviewed

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:LIPPINCOTT WILLIAMS & WILKINS  

    Objectives: This study aimed to examine expression profile of MUC4 in intraductal papillary mucinous neoplasm of the pancreas (IPMN).
    Methods: We performed immunohistochemistry (IHC) of MUC4 in 142 IPMNs, with evaluation of the specificity of 2 anti-MUC4 monoclonal antibodies, 8G7 and 1G8, in cancer cell lines.
    Results: Monoclonal antibody 8G7 showed a clear immunoreactivity, whereas MAb 1G8 did not show any immunoreactivity, in the Western blotting and IHC for human pancreatic carcinoma cell lines expressing MUC4 messenger RNA. However, IHC signals detected by both monoclonal antibodies were observed in the tissue specimens. The expression rates of MUC4/8G7 detected by MAb 8G7 and MUC4/1G8 detected by MAb 1G8 in the intestinal-type IPMNs were significantly higher than those in the gastric-type IPMNs. In the intestinal-type IPMNs, MUC4/8G7 was expressed mainly in the cytoplasm of the neoplastic cells, whereas MUC4/1G8 was expressed mainly at the cell apexes. Even in the gastric-type IPMNs with rare MUC4 expression in the low-grade dysplasia, both MUC4 expression rates increased when dysplasia advanced.
    Conclusions: A significantly higher expression of MUC4 in intestinal-type IPMNs than in gastric-type IPMNs will be one of the biomarkers to discriminate between the intestinal-type IPMNs with high malignancy potential from gastric-type IPMNs with low malignancy potential.

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  • Sho Kitamoto, Seiya Yokoyama, Michiyo Higashi, Norishige Yamada, Sonshin Takao, Suguru Yonezawa .  MUC1 enhances hypoxia-driven angiogenesis through the regulation of multiple proangiogenic factors .  ONCOGENE32 ( 39 ) 4614 - 4621   2013.9MUC1 enhances hypoxia-driven angiogenesis through the regulation of multiple proangiogenic factorsReviewed

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    Pancreatic cancer is one of the most lethal malignancies due to its aggressive growth and rapid development of distant metastases. In this context, mucin 1 (MUC1) overexpression and hypoxia are frequently observed events. However, their functional relationship remains largely unknown. This study provides evidence that MUC1 is overexpressed by hypoxia and contributes to hypoxia-driven angiogenesis. Using the conditioned medium obtained from hypoxia-stressed AsPC1 cells treated with MUC1 siRNAs, we demonstrated that MUC1 enhanced the endothelial tube formation, proliferation and migration ability, which induced by hypoxia-conditioned medium (HCM). In addition, MUC1 was significantly induced by hypoxia, especially in the pancreatic cancer cells derived from metastatic tumors (AsPC1, HPAF2 or Capan1), and MUC1-cytoplasmic tail (MUC1-CT) accumulated in the nucleus under hypoxia. As noted in a previous report, MUC1-CT was recruited to genomic regions upstream of the connective tissue growth factor (CTGF) accompanied with beta-catenin and p53, resulting in the hypoxic induction of CTGF. Moreover, hypoxia-induced MUC1 partially regulated two other hypoxia-inducible proangiogenic factors including vascular endothelial growth factor-A and platelet-derived growth factor-B. The neutralization assay revealed that endothelial tube formation induced by HCM was clearly suppressed by antibodies against these three factors, suggesting the importance of these factors in hypoxia-driven angiogenesis. In summary, this is the first report demonstrating a pivotal role of MUC1 in controlling the hypoxia-driven angiogenesis through the regulation of multiple proangiogenic factors in pancreatic cancer. Our findings provide the novel insights into the understanding of complex interactions between pancreatic cancer cells and tumor microenvironments.

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  • Yu-ki Matsuno, Weijie Dong, Seiya Yokoyama, Suguru Yonezawa, Hisashi Narimatsu, Akihiko Kameyama .  Identification of mucins by using a method involving a combination of on-membrane chemical deglycosylation and immunostaining .  JOURNAL OF IMMUNOLOGICAL METHODS394 ( 1-2 ) 125 - 30   2013.8Identification of mucins by using a method involving a combination of on-membrane chemical deglycosylation and immunostainingReviewed

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    The characterization of mucins is critically important for gaining insights into the molecular pathology of diseases, including cancers, as well as for the discovery of biomarkers for disease diagnosis. However, no practical method has yet been reported for identifying mucin proteins. Here, we report a technique for immunological identification of mucins separated by supported molecular matrix electrophoresis (SMME), a recently developed membrane electrophoresis method. The technique involves on-membrane deglycosylation of mucins by using mild periodate oxidation/base-catalyzed elimination, followed by immunostaining with an antibody that specifically recognizes the mucin tandem repeat (TR) peptide. We demonstrated the method's feasibility by using MUC1 derived from 2 cancer cell lines, 1470 and HPAF-II. The present method shows potential as an alternative approach for the identification of mucins separated by SMME or blotted from conventional gel electrophoresis, on a PVDF membrane. (C) 2013 Elsevier B.V. All rights reserved.

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  • Suguru Yonezawa, Shinichi Kitajima, Michiyo Higashi, Masahiko Osako, Michiko Horinouchi, Seiya Yokoyama, Sho Kitamoto, Norishige Yamada, Yukihiro Tamura, Takeshi Shimizu, Mineo Tabata, Masamichi Goto .  A novel anti-MUC1 antibody against the MUC1 cytoplasmic tail domain: use in sensitive identification of poorly differentiated cells in adenocarcinoma of the stomach .  GASTRIC CANCER15 ( 4 ) 370 - 81   2012.10A novel anti-MUC1 antibody against the MUC1 cytoplasmic tail domain: use in sensitive identification of poorly differentiated cells in adenocarcinoma of the stomachReviewed

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:SPRINGER  

    Isolated cancer cells of non-solid type poorly differentiated adenocarcinoma (por2) or signet-ring cell carcinoma (sig) are frequently seen in scirrhous gastric cancers with a very poor prognosis. These cells are often scattered in granulation tissue or desmoplastic fibrotic tissue and tend to be overlooked in routine pathological examination. We aimed to raise a novel antibody that can identify the isolated cancer cells easily.
    Because the MUC1 cytoplasmic tail domain (CTD) has many biological roles including tumor progression and cell adhesion disturbance and is expected to be expressed in isolated cancer cells, we raised a novel monoclonal antibody (MAb) MUC1-014E against an intracellular nonrepeating 19-amino-acid sequence (RYVPPSSTDRSPYEKVSAG: N-1217-1235-C) of the MUC1 CTD, using a synthetic peptide including the 7-amino-acid epitope (STDRSPY: N-1223-1229-C).
    In the immunohistochemical staining of 107 gastrectomy specimens including 48 por2 and 31 sig lesions, the MAb MUC1-014E showed high rates of positive staining (a parts per thousand yen5% of carcinoma cells stained) for por2 (100%) and sig (97%), and of the highest intensity staining (4+, a parts per thousand yen75% of carcinoma cells stained) for por2 (100%) and sig (90%). In the 89 biopsy specimens including 82 por2 and 38 sig lesions, the MAb MUC1-014E showed high rates of positive staining for por2 (100%) and sig (100%) and of 4+ staining for por2 (87%) and sig (84%). All the rates were significantly higher than those with cytokeratins (AE1/AE3 or CAM5.2).
    The MAb MUC1-014E is very useful for accurate detection of isolated cancer cells in scirrhous gastric cancers.

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  • Satoshi Nagata, Tomofumi Hamada, Norishige Yamada, Seiya Yokoyama, Sho Kitamoto, Yuji Kanmura, Masahiro Nomura, Yoshiaki Kamikawa, Suguru Yonezawa, Kazumasa Sugihara .  Aberrant DNA methylation of tumor-related genes in oral rinse A Noninvasive Method for Detection of Oral Squamous Cell Carcinoma .  CANCER118 ( 17 ) 4298 - 308   2012.9Aberrant DNA methylation of tumor-related genes in oral rinse A Noninvasive Method for Detection of Oral Squamous Cell CarcinomaReviewed

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    BACKGROUND: The early detection of oral squamous cell carcinoma (OSCC) is important, and a screening test with high sensitivity and specificity is urgently needed. Therefore, in this study, the authors investigated the methylation status of tumor-related genes with the objective of establishing a noninvasive method for the detection of OSCC. METHODS: Oral rinse samples were obtained from 34 patients with OSCC and from 24 healthy individuals (controls). The methylation status of 13 genes was determined by using methylation-specific polymerase chain reaction analysis and was quantified using a microchip electrophoresis system. Promoter methylation in each participant was screened by receiver operating characteristic analysis, and the utility of each gene's methylation status, alone and in combination with other genes, was evaluated as a tool for oral cancer detection. RESULTS: Eight of the 13 genes had significantly higher levels of DNA methylation in samples from patients with OSCC than in controls. The genes E-cadherin (ECAD), transmembrane protein with epidermal growth factor-like and 2 follistatin-like domains 2 (TMEFF2), retinoic acid receptor beta (RAR beta), and O-6 methylguanine DNA methyltransferase (MGMT) had high sensitivity (&gt;75%) and specificity for the detection of oral cancer. OSCC was detected with 100% sensitivity and 87.5% specificity using a combination of ECAD, TMEFF2, RAR beta, and MGMT and with 97.1% sensitivity and 91.7% specificity using a combination of ECAD, TMEFF2, and MGMT. CONCLUSIONS: The aberrant methylation of a combination of marker genes present in oral rinse samples was used to detect OSCC with &gt;90% sensitivity and specificity. The detection of methylated marker genes from oral rinse samples has great potential for the noninvasive detection of OSCC. Cancer 2012. (c) 2012 American Cancer Society.

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  • Seiya Yokoyama, Sho Kitamoto, Norishige Yamada, Izumi Houjou, Tamotsu Sugai, Shin-ichi Nakamura, Yoshifumi Arisaka, Kyoichi Takaori, Michiyo Higashi, Suguru Yonezawa .  The application of methylation specific electrophoresis (MSE) to DNA methylation analysis of the 5 ' CpG island of mucin in cancer cells .  BMC CANCER12   67   2012.2The application of methylation specific electrophoresis (MSE) to DNA methylation analysis of the 5 ' CpG island of mucin in cancer cellsReviewed

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    Background: Methylation of CpG sites in genomic DNA plays an important role in gene regulation and especially in gene silencing. We have reported mechanisms of epigenetic regulation for expression of mucins, which are markers of malignancy potential and early detection of human neoplasms. Epigenetic changes in promoter regions appear to be the first step in expression of mucins. Thus, detection of promoter methylation status is important for early diagnosis of cancer, monitoring of tumor behavior, and evaluating the response of tumors to targeted therapy. However, conventional analytical methods for DNA methylation require a large amount of DNA and have low sensitivity.
    Methods: Here, we report a modified version of the bisulfite-DGGE (denaturing gradient gel electrophoresis) using a nested PCR approach. We designated this method as methylation specific electrophoresis (MSE). The MSE method is comprised of the following steps: (a) bisulfite treatment of genomic DNA, (b) amplification of the target DNA by a nested PCR approach and (c) applying to DGGE. To examine whether the MSE method is able to analyze DNA methylation of mucin genes in various samples, we apply it to DNA obtained from state cell lines, ethanol-fixed colonic crypts and human pancreatic juices.
    Result: The MSE method greatly decreases the amount of input DNA. The lower detection limit for distinguishing different methylation status is &lt; 0.1% and the detectable minimum amount of DNA is 20 pg, which can be obtained from only a few cells. We also show that MSE can be used for analysis of challenging samples such as human isolated colonic crypts or human pancreatic juices, from which only a small amount of DNA can be extracted.
    Conclusions: The MSE method can provide a qualitative information of methylated sequence profile. The MSE method allows sensitive and specific analysis of the DNA methylation pattern of almost any block of multiple CpG sites. The MSE method can be applied to analysis of DNA methylation status in many different clinical samples, and this may facilitate identification of new risk markers.

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  • Nagata S, Hamada T, Yamada N, Yokoyama S, Kitamoto S, Kanmura Y, Nomura M, Kamikawa Y, Yonezawa S, Sugihara K .  Aberrant DNA Methylation of Tumor-related Genes in Oral Rinse is a Promising Marker for Noninvasive Detection/Screening of Oral Squamous Cell Carcinoma. .  Cancer   2012Aberrant DNA Methylation of Tumor-related Genes in Oral Rinse is a Promising Marker for Noninvasive Detection/Screening of Oral Squamous Cell Carcinoma. Reviewed

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  • Higashi M, Yamada N, Yokoyama S, Kitamoto S, Tabata K, Koriyama C, Batra SK, Yonezawa S .  Pathobiological Implications of Expression of MUC16/CA125 in Intrahepatic Cholangiocarcinoma-Mass Forming type. .  Pathobiology   2012Pathobiological Implications of Expression of MUC16/CA125 in Intrahepatic Cholangiocarcinoma-Mass Forming type. Reviewed

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  • Yonezawa S, Kitajima S, Higashi M, Osako M, Horinouchi M, Yokoyama S, Kitamoto S, Yamada N, Tamura K, Shimizu T, Tabata M, Goto M .  A novel anti-MUC1 antibody against the MUC1 cytoplasmic tail domain: use in sensitive identification of poorly differentiated cells in adenocarcinoma of the stomach .  Gastric Cancer   2012A novel anti-MUC1 antibody against the MUC1 cytoplasmic tail domain: use in sensitive identification of poorly differentiated cells in adenocarcinoma of the stomachReviewed

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  • Sho Kitamoto, Seiya Yokoyama, Michiyo Higashi, Norishige Yamada, Shyuichiro Matsubara, Sonshin Takao, Surinder K. Batra, Suguru Yonezawa .  Expression of MUC17 Is Regulated by HIF1α-mediated Hypoxic Responses and Requires a Methylation-free Hypoxia Responsible Element in Pancreatic Cancer. .  PLoS ONE7 ( 9 ) e44108 - doi: 10.1371/journal.pone.0044108.   2012Expression of MUC17 Is Regulated by HIF1α-mediated Hypoxic Responses and Requires a Methylation-free Hypoxia Responsible Element in Pancreatic Cancer. Reviewed

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  • Tamura Y, Higashi M, Kitamoto S, Yokoyama S, Osako M, Horinouchi M, Shimizu T, Tabata M, Batra SK, Goto M, Yonezawa S. .  MUC4 and MUC1 expression in adenocarcinoma of the stomach correlates with vessel invasion and lymph node metastasis: an immunohistochemical study of early gastric cancer. .  PLoS One7 ( 11 ) e49251 - doi: 10.1371/journal.pone.0049251.   2012MUC4 and MUC1 expression in adenocarcinoma of the stomach correlates with vessel invasion and lymph node metastasis: an immunohistochemical study of early gastric cancer.Reviewed

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  • Sho Kitamoto, Seiya Yokoyama, Michiyo Higashi, Norishige Yamada, Shyuichiro Matsubara, Sonshin Takao, Surinder K. Batra, Suguru Yonezawa .  Expression of MUC17 Is Regulated by HIF1 alpha-Mediated Hypoxic Responses and Requires a Methylation-Free Hypoxia Responsible Element in Pancreatic Cancer .  PLOS ONE7 ( 9 ) e44108   2012Expression of MUC17 Is Regulated by HIF1 alpha-Mediated Hypoxic Responses and Requires a Methylation-Free Hypoxia Responsible Element in Pancreatic CancerReviewed

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    MUC17 is a type 1 membrane-bound glycoprotein that is mainly expressed in the digestive tract. Recent studies have demonstrated that the aberrant overexpression of MUC17 is correlated with the malignant potential of pancreatic ductal adenocarcinomas (PDACs); however, the exact regulatory mechanism of MUC17 expression has yet to be identified. Here, we provide the first report of the MUC17 regulatory mechanism under hypoxia, an essential feature of the tumor microenvironment and a driving force of cancer progression. Our data revealed that MUC17 was significantly induced by hypoxic stimulation through a hypoxia-inducible factor 1 alpha (HIF1 alpha)-dependent pathway in some pancreatic cancer cells ( e. g., AsPC1), whereas other pancreatic cancer cells (e.g., BxPC3) exhibited little response to hypoxia. Interestingly, these low-responsive cells have highly methylated CpG motifs within the hypoxia responsive element (HRE, 5'-RCGTG-3'), a binding site for HIF1a. Thus, we investigated the demethylation effects of CpG at HRE on the hypoxic induction of MUC17. Treatment of low-responsive cells with 5-aza-2'-deoxycytidine followed by additional hypoxic incubation resulted in the restoration of hypoxic MUC17 induction. Furthermore, DNA methylation of HRE in pancreatic tissues from patients with PDACs showed higher hypomethylation status as compared to those from non-cancerous tissues, and hypomethylation was also correlated with MUC17 mRNA expression. Taken together, these findings suggested that the HIF1 alpha-mediated hypoxic signal pathway contributes to MUC17 expression, and DNA methylation of HRE could be a determinant of the hypoxic inducibility of MUC17 in pancreatic cancer cells.

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  • Michiyo Higashi, Norishige Yamada, Seiya Yokoyama, Sho Kitamoto, Kazuhiro Tabata, Chihaya Koriyama, Surinder K. Batra, Suguru Yonezawa .  Pathobiological Implications of MUC16/CA125 Expression in Intrahepatic Cholangiocarcinoma-Mass Forming Type .  PATHOBIOLOGY79 ( 2 ) 101 - 6   2012Pathobiological Implications of MUC16/CA125 Expression in Intrahepatic Cholangiocarcinoma-Mass Forming TypeReviewed

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    Objectives: MUC16 carries the peptide epitope CA125, which is well known as a marker of ovarian cancer. High serum levels of MUC16 (CA125) have been reported not only in patients with ovarian cancer but also in patients with liver diseases. We evaluated the expression of MUC16 in intrahepatic cholangiocarcinoma-mass forming type (ICC-ME) tissues. Methods: We examined the expression of MUC16 by immunohistochemical analyses using the monoclonal antibody M11 in ICC-MF tissues from 63 patients. To compare the prevalence of each mucin expression by clinicopathological features, appropriate statistical analysis was performed. Results: MUC16 was detected in 48% of samples (30/63). After adjusting for the effects of other prognostic factors, multi-variate survival analysis revealed that MUC16 expression is a significant independent factor of poor prognosis (p = 0.005). Conclusion:The current results indicate that MUC16 expression is a prognostic factor of poor survival in ICC-MF. Copyright (C) 2012 S. Karger AG, Basel

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  • Yukihiro Tamura, Michiyo Higashi, Sho Kitamoto, Seiya Yokoyama, Masahiko Osako, Michiko Horinouchi, Takeshi Shimizu, Mineo Tabata, Surinder K. Batra, Masamichi Goto, Suguru Yonezawa .  MUC4 and MUC1 Expression in Adenocarcinoma of the Stomach Correlates with Vessel Invasion and Lymph Node Metastasis: An Immunohistochemical Study of Early Gastric Cancer .  PLOS ONE7 ( 11 ) e49251   2012MUC4 and MUC1 Expression in Adenocarcinoma of the Stomach Correlates with Vessel Invasion and Lymph Node Metastasis: An Immunohistochemical Study of Early Gastric CancerReviewed

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    We have previously reported that MUC4 expression is a poor prognostic factor in various carcinomas. Our previous study also showed that MUC1 expression in gastric cancers, including the early and advanced stages is a poor prognostic factor. In the present study, the expression profiles of MUC4 and MUC1 were examined by immunohistochemistry (IHC) using two anti-MUC4 monoclonal antibodies (MAbs), 8G7 and 1G8, and anti-MUC1 MAb DF3 in 104 gastrectomy specimens of early gastric adenocarcinoma with submucosal invasion (pT1b2), including 197 histological subtype lesions. Before the IHC study of the human specimens, we evaluated the specificity of the two MAbs by Western blotting and IHC of two MUC4 mRNA expressing gastric cancer cell lines. MAb 8G7 reacted clearly, whereas MAb 1G8 did not show any reactivity, in either Western blotting or IHC. In the IHC of the gastric cancers, the expression rates of MUC4/8G7 detected by MAb 8G7, MUC4/1G8 detected by MAb 1G8 and MUC1/DF3 detected by MAb DF3 in well differentiated types (70%, 38/54; 67%, 36/54; 52%, 28/54) were significantly higher than those in poorly differentiated types (18%, 10/55; 36%, 20/55; 13%, 7/55) (P&lt;0.0001; P = 0.0021; P&lt;0.0001), respectively. The MUC4/8G7 expression was related with lymphatic invasion (r = 0.304, P = 0.033). On the other hand, the MUC4/1G8 expression was related with lymphatic invasion (r = 0.395, P = 0.001) and lymph node metastasis (r = 0.296, P = 0.045). The MUC1/DF3 expression was related with lymphatic invasion (r = 0.357, P = 0.032) and venous invasion (r = 0.377, P = 0.024). In conclusion, the expression of MUC4 as well as MUC1 in early gastric cancers is a useful marker to predict poor prognostic factors related with vessel invasion.

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  • Suguru Yonezawa, Michiyo Higashi, Norishige Yamada, Seiya Yokoyama, Sho Kitamoto, Shinichi Kitajima, Masamichi Goto .  Mucins in human neoplasms: Clinical pathology, gene expression and diagnostic application .  PATHOLOGY INTERNATIONAL61 ( 12 ) 697 - 716   2011.12Mucins in human neoplasms: Clinical pathology, gene expression and diagnostic applicationReviewed

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    Mucins are high molecular weight glycoproteins that play important roles in carcinogenesis and tumor invasion. Our immunohistochemical studies demonstrated that MUC1 or MUC4 expression is related to the aggressive behavior and poor outcome of human neoplasms. MUC2 is expressed in indolent pancreatobiliary neoplasms, but these tumors sometimes show invasive growth with MUC1 expression in invasive areas. MUC5AC shows de novo high expression in many types of precancerous lesions of pancreatobiliary cancers and is an effective marker for early detection of the neoplasms. The combination of MUC1, MUC2, MUC4 and MUC5AC expression may be useful for early detection and evaluation of the potential for malignancy of pancreatobiliary neoplasms. Regarding the mechanism of mucin expression, we have recently reported that expression of the mucin genes is regulated epigenetically in cancer cell lines, using quantitative MassARRAY analysis, methylation-specific polymerase chain reaction analysis and chromatin immunoprecipitation analysis, with confirmation by the treatment with 5-aza-2'-deoxycytidine and trichostatin A. We have also developed a monoclonal antibody against the MUC1 cytoplasmic tail domain, which has many biological roles. Based on all of the above findings, we suggest that translational research into mucin gene expression mechanisms, including epigenetics, may provide new tools for early and accurate detection of human neoplasms.

    DOI: 10.1111/j.1440-1827.2011.02734.x

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  • Norishige Yamada, Sho Kitamoto, Seiya Yokoyama, Tomofumi Hamada, Masamichi Goto, Hideaki Tsutsumida, Michiyo Higashi, Suguru Yonezawa .  Epigenetic regulation of mucin genes in human cancers .  Clinical Epigenetics2 ( 2 ) 85 - 96   2011.8Epigenetic regulation of mucin genes in human cancersReviewed

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    Mucins are high molecular weight glycoproteins that play important roles in diagnostic and prognostic prediction and in carcinogenesis and tumor invasion. Regulation of expression of mucin genes has been studied extensively, and signaling pathways, transcriptional regulators, and epigenetic modification in promoter regions have been described. Detection of the epigenetic status of cancerrelated mucin genes is important for early diagnosis of cancer and for monitoring of tumor behavior and response to targeted therapy. Effects of micro-RNAs on mucin gene expression have also started to emerge. In this review, we discuss the current views on epigenetic mechanisms of regulation of mucin genes (MUC1, MUC2, MUC3A, MUC4, MUC5AC, MUC5B, MUC6, MUC16, and MUC17) and the possible clinical applications of this epigenetic information. © Springer-Verlag 2011.

    DOI: 10.1007/s13148-011-0037-3

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  • Yu-Ki Matsuno, Weijie Dong, Seiya Yokoyama, Suguru Yonezawa, Takuro Saito, Mitsukazu Gotoh, Hisashi Narimatsu, Akihiko Kameyama .  Improved method for immunostaining of mucin separated by supported molecular matrix electrophoresis by optimizing the matrix composition and fixation procedure .  ELECTROPHORESIS32 ( 14 ) 1829 - 36   2011.7Improved method for immunostaining of mucin separated by supported molecular matrix electrophoresis by optimizing the matrix composition and fixation procedureReviewed

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    Mucins are a family of heavily glycosylated high molecular mass proteins that have great potential as novel clinical biomarkers for the diagnosis of various malignant tumors. Supported molecular matrix electrophoresis (SMME) is a new type of membrane electrophoresis that can be used to characterize mucins. In SMME, mucins migrate in a molecular matrix supported by membrane materials. Here, we have developed an immunostaining method for the identification of SMME-separated mucins. The novel method involves stably fixing the mucins onto the SMME membrane and optimizing the molecular matrix for the fixation process. We applied this technique for the detection of MUC1 produced from three cancer cell lines (T47D, HPAF-II and BxPC3) and also analyzed their O-linked glycans by mass spectrometry. Our results revealed that properties of the MUC1 molecules from the three cell lines are different in terms of migrating position in SMME and glycan profile. The present method allows simple and rapid characterization of mucins in terms of both glycans and core proteins. The method will be a useful tool for the exploration of mucin alterations associated with various diseases such as cancer.

    DOI: 10.1002/elps.201000608

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  • Kitamoto S, Yamada N, Yokoyama S, Houjou I, Higashi M, Goto M, Batra SK, Yonezawa S. .  DNA methylation and histone H3-K9 modifications contribute to MUC17 expression. .  Glycobiology21 ( 2 ) 247 - 256   2011.2DNA methylation and histone H3-K9 modifications contribute to MUC17 expression.Reviewed

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  • Sho Kitamoto, Norishige Yamada, Seiya Yokoyama, Izumi Houjou, Michiyo Higashi, Masamichi Goto, Surinder K. Batra, Suguru Yonezawa .  DNA methylation and histone H3-K9 modifications contribute to MUC17 expression .  GLYCOBIOLOGY21 ( 2 ) 247 - 56   2011.2DNA methylation and histone H3-K9 modifications contribute to MUC17 expressionReviewed

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:OXFORD UNIV PRESS INC  

    MUC17 glycoprotein is a membrane-associated mucin that is mainly expressed in the digestive tract. It has been suggested that MUC17 expression is correlated with the malignancy potential of pancreatic ductal adenocarcinomas (PDACs). In the present study, we provided the first report of the MUG! 7 gene expression through epigenetic regulation such as promoter methylation, histone modification and microRNA (miRNA) expression. Near the transcriptional start site, the DNA methylation level of MUC17-negative cancer cell lines (e.g. PANC1) was high, whereas that of MUC17-positive cells (e.g. AsPC-1) was low. Histone H3-K9 (H3-K9) modification status was also closely related to MUC17 expression. Our results indicate that DNA methylation and histone H3-K9 modification in the 5&apos; flanking region play a critical role in MUC17 expression. Furthermore, the hypomethylation status was observed in patients with PDAC. This indicates that the hypomethylation status in the MUC17 promoter could be a novel epigenetic marker for the diagnosis of PDAC. In addition, the result of miRNA microarray analysis showed that five potential miRNA candidates existed. It is also possible that the MUC17 might be post-transcriptionally regulated by miRNA targeting to the 3&apos;-untranslated region of its mRNA. These understandings of the epigenetic changes of MUC17 may be of importance for the diagnosis of carcinogenic risk and the prediction of outcomes for cancer patients.

    DOI: 10.1093/glycob/cwq155

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  • Matsuno Y, Dong W, Yokoyama S, Yonezawa S, Narimatsu H, Kameyama A .  Improved method for immunostaining of mucin separated by supported molecular matrix electrophoresis by optimizing the matrix composition and fixation procedure. .  Electrophoresis32 ( 14 ) 1829 - 1836   2011Improved method for immunostaining of mucin separated by supported molecular matrix electrophoresis by optimizing the matrix composition and fixation procedure.Reviewed

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  • Norishige Yamada, Yukari Nishida, Seiya Yokoyama, Hideaki Tsutsumida, Izumi Houjou, Sho Kitamoto, Masamichi Goto, Michiyo Higashi, Suguru Yonezawa .  Expression of MUC5AC, an early marker of pancreatobiliary cancer, is regulated by DNA methylation in the distal promoter region in cancer cells .  JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES17 ( 6 ) 844 - 54   2010.11Expression of MUC5AC, an early marker of pancreatobiliary cancer, is regulated by DNA methylation in the distal promoter region in cancer cellsReviewed

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:SPRINGER TOKYO  

    High de novo expression of MUC5AC (a gastric-type secreted mucin) is observed in many types of pancreatobiliary neoplasms, including precursor lesions. In this study, we show that the DNA methylation pattern is intimately correlated with MUC5AC expression in ten cancer cell lines (breast, lung, pancreas, and colon).
    The CpG methylation status of the MUC5AC promoter from -3855 to +321 was mapped using MassARRAY analysis, which utilizes base-specific cleavage of nucleic acids. ChIP assays and micro-RNA (miRNA) microarray expression profiling were also carried out in both MUC5AC-positive cells and in those with no or low MUC5AC expression.
    In the distal region from -3718 to -3670 of the promoter, MUC5AC-negative cancer cells (e.g., MDA-MB-453) were highly methylated, whereas MUC5AC-positive cells (e.g., MCF-7) had low methylation levels. The modification status of histone H3 lysine 9 (H3-K9) was also closely related to MUC5AC expression. Expression levels of miRNAs in the cancer cells were not correlated with MUC5AC expression.
    Our results indicate that MUC5AC is regulated by CpG methylation and histone H3-K9 modification of the MUC5AC promoter distal region, but not by miRNAs. An understanding of the epigenetic regulation of MUC5AC may be of importance for the diagnosis of carcinogenic risk in the pancreatobiliary system.

    DOI: 10.1007/s00534-010-0278-0

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  • Sho Kitamoto, Norishige Yamada, Seiya Yokoyama, Izumi Houjou, Michiyo Higashi, Suguru Yonezawa .  Promoter hypomethylation contributes to the expression of MUC3A in cancer cells .  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS397 ( 2 ) 333 - 9   2010.6Promoter hypomethylation contributes to the expression of MUC3A in cancer cellsReviewed

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    MUC3A is a membrane-bound glycoprotein that is aberrantly expressed in carcinomas and is a risk factor for a poor prognosis. However, the exact mechanism of MUC3A expression has yet to be clarified. Here, we provide the first evidence that MUC3A gene expression is controlled by the CpG methylation status of the proximal promoter region. We show that the DNA methylation pattern is intimately correlated with MUC3A expression in breast, lung, pancreas and colon cancer cell lines. The DNA methylation status of 30 CpG sites from -660 to +273 was mapped using MassARRAY analysis. MUC3A-negative cancer cell lines and those with low MUC3A expression (e.g., MCF-7) were highly methylated in the proximal promoter region, corresponding to 9 CpG sites (-345 to -75 bp), whereas MUC3A-positive cell lines (e.g., LS174T) had low methylation levels. Moreover, 5-aza-2'-deoxycytidine and trichostatin A treatment of MUC3A-negative cells or those with low MUC3A expression caused elevation of MUC3A mRNA. Our results suggest that DNA hypomethylation in the 5'-flanking region of the MUC3A gene plays an important role in MUC3A expression in carcinomas of various organs. An understanding of epigenetic changes in MUC3A may contribute to the diagnosis of carcinogenic risk and to prediction of outcome in patients with cancer. (C) 2010 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.bbrc.2010.05.124

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  • Suguru Yonezawa, Michiyo Higashi, Norishige Yamada, Seiya Yokoyama, Masamichi Goto .  Significance of mucin expression in pancreatobiliary neoplasms .  JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES17 ( 2 ) 108 - 24   2010.3Significance of mucin expression in pancreatobiliary neoplasmsReviewed

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    Mucins are high molecular weight glycoproteins that play important roles in carcinogenesis and tumor invasion. We have described, for the first time, that pancreatic ductal adenocarcinomas (PDACs) with an aggressive behavior and a poor outcome expressed MUC1 (pan-epithelial membrane-associated mucin) but did not express MUC2 (intestinal-type secreted mucin), whereas intraductal papillary mucinous neoplasms (IPMNs) with indolent behavior and a favorable outcome did not express MUC1 but did express MUC2. These expression profiles of MUC1 and MUC2 related to the prognoses of the patients were also observed in biliary neoplasms such as intrahepatic cholangiocarcinoma (ICC)-mass-forming type (MF), mucin-producing bile duct tumor (MPBT), and extrahepatic bile duct carcinoma (EHBDC). We also found recently that high expression of MUC4 (tracheobronchial membrane-associated mucin) in PDACs, ICCs-MF, and EHBDCs was a new independent poor prognostic factor, although MUC4 was not expressed in normal pancreatobiliary tissue. High de novo expression of MUC5AC (gastric-type secreted mucin) was observed in many types of pancreatobiliary neoplasms, including all grades of pancreatic intraepithelial neoplasia (PanIN) and biliary intraepithelial neoplasia (BilIN), and all types of IPMNs and MPBTs, as well as PDACs and ICCs-MF, although MUC5AC was not expressed in normal pancreatobiliary tissue. The combined status of MUC1, MUC2, MUC4, and MUC5AC expression may be useful for the early detection of pancreatobiliary neoplasms and evaluation of their malignancy. In regard to the mechanism of mucin expression, we have recently reported that MUC1, MUC2, MUC4, and MUC5AC gene expression is regulated by epigenetics (DNA methylation and histone H3 lysine 9 modification) in cancer cell lines, including PDAC cells. Translational research of mucin gene expression mechanisms, including epigenetics, in pancreatobiliary neoplasms may give us new tools for the early and accurate detection of these neoplasms.

    DOI: 10.1007/s00534-009-0174-7

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  • Kitamoto S, Yamada N, Yokoyama S, Houjou I, Higashi M, Yonezawa S .  Promoter hypomethylation contributes to the expression of MUC3A in cancer cells .  Biochem Biophys Res Commun397 ( 2 ) 333 - 339   2010Promoter hypomethylation contributes to the expression of MUC3A in cancer cellsReviewed

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  • Yamada N, Nishida Y, Yokoyama S, Tsutsumida H, Houjou I, Kitamoto S, Goto M, Higashi M, Yonezawa S .  Expression of MUC5AC, an early marker of pancreatobiliary cancer, is regulated by DNA methylation in the distal promoter region in cancer cells. .  J Hepatobiliary Pancreat Sci17 ( 6 ) 844 - 854   2010Expression of MUC5AC, an early marker of pancreatobiliary cancer, is regulated by DNA methylation in the distal promoter region in cancer cells.Reviewed

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  • Seiya Yokoyama, Yuto Iida, Yousuke Kawasaki, Yuji Minami, Keiichi Watanabe, Fumio Yagi .  The chitin-binding capability of Cy-AMP1 from cycad is essential to antifungal activity .  JOURNAL OF PEPTIDE SCIENCE15 ( 7 ) 492 - 7   2009.7The chitin-binding capability of Cy-AMP1 from cycad is essential to antifungal activityReviewed

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:JOHN WILEY & SONS LTD  

    Antimicrobial peptides are important components of the host innate immune responses by exerting broad-spectrum microbicidal activity against pathogenic microbes. Cy-AMP1 found in the cycad (Cycas revoluta) seeds has chitin-binding ability, and the chitin-binding domain was conserved in knottin-type and hevein-type antimicrobial peptides. The recombinant Cy-AMP1 was expressed in Escherichia coli and purified to study the role of chitin-binding domain. The mutants of Cy-AMP1 lost chitin-binding ability completely, and its antifungal activity was markedly decreased in comparison with native Cy-AMP1. However, the antimicrobial activities of the mutant peptides are nearly identical to that of native one. It was suggested that the chitin-binding domain plays an essential role in antifungal, but not antimicrobial, activity of Cy-AMP1. Copyright (C) 2009 European Peptide Society and John Wiley & Sons, Ltd.

    DOI: 10.1002/psc.1147

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  • Seiya Yokoyama, Kouji Kato, Atsuko Koba, Yuji Minami, Keiichi Watanabec, Fumio Yagi .  Purification, characterization, and sequencing of antimicrobial peptides, Cy-AMP1, Cy-AMP2, and Cy-AMP3, from the Cycad (Cycas reuoluta) seeds .  PEPTIDES29 ( 12 ) 2110 - 7   2008.12Purification, characterization, and sequencing of antimicrobial peptides, Cy-AMP1, Cy-AMP2, and Cy-AMP3, from the Cycad (Cycas reuoluta) seedsReviewed

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:ELSEVIER SCIENCE INC  

    Novel antimicrobial peptides (AMP), designated Cy-AMP1, Cy-AMP2, and Cy-AMP3, were purified from seeds of the cycad (Cycas revoluta) by a CM cellulofine column, ion-exchange HPLC on SP COSMOGEL, and reverse-phase HPLC. They had molecular masses of 4583.2 Da, 4568.9 Da and 9275.8 Da, respectively, by MALDI-TOF MS analysis. Half of the amino acid residues of Cy-AMP1 and Cy-AMP2 were cysteine, glycine and proline, and their sequences were similar. The sequence of Cy-AMP3 showed high homology to various lipid transfer proteins. For Cy-AMP1 and Cy-AMP2, the concentrations of peptides required for 50% inhibition (IC(50)) of the growth of plant pathogenic fungi, Gram-positive and Gram-negative bacteria were 7.0-8.9 mu g/ml. The Cy-AMP3 had weak antimicrobial activity. The structural and antimicrobial characteristics of Cy-AMP1 and Cy-AMP2 indicated that they are a novel type of antimicrobial peptide belonging to a plant defensin family. (c) 2008 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.peptides.2008.08.007

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Books

  • Gene Regulation and Therapeutics for Cancer International journal

    Michiyo Higashi, Seiya Yokoyama( Role: Contributor ,  Aberrant Methylation of UC Promoters in Human Pancreatic Ductal Carcinomas)

    CRC press  2021.3 

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    Total pages:166   Responsible for pages:151-162   Language:English Book type:Scholarly book

    Pancreatic ductal adenocarcinoma (PDAC) is still a lethal disease in spite of the improvement in diagnosis and treatment. The overall five-year survival rate for all patients with or without pancreatectomy after diagnosis is 13% in Japan [1]. On the other hand, patients with a successful resection of PDAC at an early stage (Stage IA: tumors located within pancreas; tumor size< 2 cm, without metastasis) have a 46% five year survival rate [1, 2]. However, most patients with PDAC are diagnosed in the advanced stages because of the anatomical location of the pancreas, lack of specific symptoms, infiltration to the surrounding organs, or distant metastasis even from a small primary tumor less than 2 cm in diameter. Thus, a diagnostic technique for small pancreatic adenocarcinomas without symptoms is urgently needed. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in pancreatic neoplasms. MUC1 and MUC4 are large membrane-bound glycoproteins that are translated as single polypeptides. These mucins undergo intracellular autocatalytic proteolytic cleavage into two subunits that form stable non-covalent heterodimers that are transported to the cell surface. MUC1 contributes to oncogenesis by promoting the loss of epithelial cell polarity, promoting growth and survival pathways, activating

MISC

  • 【IPMN大全】IPMNの歴史的変遷 IPMNにおけるMUC発現とその評価の歴史

    東 美智代, 横山 勢也, 米澤 傑, 谷本 昭英

    胆と膵   41 ( 臨増特大 )   1159 - 1162   2020.11

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    Language:Japanese   Publisher:医学図書出版(株)  

    膵管内乳頭粘液性腫瘍(intraductal papillary mucinous neoplasm:IPMN)の大きな特徴は「粘液の産生」である。ムチンは「粘液」の主成分であり、細胞の保護を行い恒常性維持に大きな役目を果たしている。ムチンの骨格であるコア蛋白が「MUC」という総称でよばれており、クローニングされた順に番号が付いている。IPMNは亜型によってMUCの発現形式が異なっていることは現在ではよく知られている。しかし、IPMNが認識されはじめた当初はMUC2(+)の症例がほとんどであった。症例数の蓄積とともにMUC2(-)の症例が認識され、臨床病理学的特徴も大きく異なることがわかり、2004年頃に亜型として確立された。MUC発現は亜型のみでなく予後などの悪性度とも関連しており、早期診断などへの臨床応用も期待される。(著者抄録)

  • 膵癌におけるメチル化によるムチン発現調節

    横山勢也、東美智代、谷本昭英、米澤傑

    肝胆膵   76 ( 5 )   2018.5

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)   Publisher:アークメディア  

  • 【肝胆膵疾患のエピジェネティクスを学ぶ】膵疾患のエピジェネティクス 膵癌におけるメチル化によるムチン発現調節

    横山 勢也, 東 美智代, 谷本 昭英, 米澤 傑

    肝・胆・膵   76 ( 5 )   945 - 950   2018.5

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  • 【肝胆膵疾患のエピジェネティクスを学ぶ】 膵疾患のエピジェネティクス 膵癌におけるメチル化によるムチン発現調節

    横山 勢也, 東 美智代, 谷本 昭英, 米澤 傑

    肝・胆・膵   76 ( 5 )   945 - 950   2018.5

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  • MUC1およびMUC4遺伝子のメチル化解析による膵癌摘出術後の予後評価(Aberrant methylation of MUC1 and MUC4 are potential risk marker for prognosis after surgery of PDAC)

    横山 勢也, 東 美智代, 谷本 昭英

    日本病理学会会誌   107 ( 1 )   314 - 315   2018.4

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    Language:English   Publisher:(一社)日本病理学会  

  • 革新的ライフサイエンスの展望 新規DNAメチル化解析法による新しい予後マーカーの開発

    横山勢也, 東美智代

    化学工業   67 ( 7 )   483‐488 - 488   2016.7

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    Language:Japanese  

    CiNii Books

    J-GLOBAL

  • 胆嚢癌におけるムチン発現の検討と予後との関連(Analysis of the relation between mucin expression and prognosis of gallbladder carcinoma)

    平木 翼, 北薗 育美, 後藤 優子, 田崎 貴嗣, 霧島 茉莉, 横山 勢也, 東 美智代, 畑中 一仁, 谷本 昭英

    日本病理学会会誌   105 ( 1 )   447 - 447   2016.4

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  • 次世代ライフサイエンスの展望 新規DNAメチル化解析法の開発と応用

    横山勢也, 北本祥, 山田宗茂, 東美智代, 米澤傑

    化学工業   66 ( 1 )   28 - 33   2015.1

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    J-GLOBAL

  • 膵腫瘍の早期診断マーカーとしての膵液中ムチン発現の解析

    新原亨, 岩木宏介, 豊田真理, 西俣寛人, 田中貞夫, 米澤傑, 東美智代, 横山勢也, 後藤優子

    月刊臨床と研究   91 ( 11 )   1527 - 1528   2014.11

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    J-GLOBAL

  • 膵腫瘍の早期診断マーカーとしての膵液中ムチン発現の解析

    新原 亨, 岩木 宏介, 豊田 真理, 西俣 寛人, 田中 貞夫, 米澤 傑, 東 美智代, 横山 勢也, 後藤 優子

    臨牀と研究   91 ( 11 )   1527 - 1528   2014.11

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    Language:Japanese   Publisher:大道学館出版部  

  • 膵液中ムチン遺伝子発現の高感度DNAメチル化解析(MSE法)による膵癌早期診断

    米澤傑, 横山勢也, 東美智代

    すい臓   29 ( 3 )   451   2014.6

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    J-GLOBAL

  • COPDを改めて問う 基礎医学とのダイアローグ エピジェネティクスによるムチン発現制御

    米澤傑, 横山勢也, 山田宗茂, 北本祥, 東美智代

    Lung Perspect   22 ( 2 )   185-190,118   2014.5

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    J-GLOBAL

  • 【COPDを改めて問う】 基礎医学とのダイアローグ エピジェネティクスによるムチン発現制御

    米澤 傑, 横山 勢也, 山田 宗茂, 北本 祥, 東 美智代

    THE LUNG-perspectives   22 ( 2 )   185 - 190   2014.5

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    Language:Japanese   Publisher:(株)メディカルレビュー社  

    さまざまなヒト腫瘍において、MUC1(汎上皮性膜結合ムチン)は予後不良因子であり、MUC2(腸型分泌ムチン)は予後良好因子である。また、MUC4(気管支型膜結合ムチン)高発現はさらなる予後不良に関連している。これらのムチンの遺伝子発現には、DNAメチル化とヒストン修飾というエピジェネティクスが関連している。われわれは、ヒトサンプルのような夾雑な検体の解析が可能な新規DNAメチル化解析法「methylation specific electrophoresis(MSE)」を開発し、膵液内のMUC1・MUC2・MUC4をMSEで解析することにより、高い感度と精度をもって、診断の難しい膵腫瘍を早期に正確に診断するシステムを構築した。現在、肺癌におけるムチン発現の研究をベースとして、ヒト肺癌組織におけるMUC1とMUC4の「MSE」による解析が進んでおり、喀痰や気管支肺胞洗浄液を用いて、ムチンのエピジェネティクスを応用した肺癌早期診断の扉が開かれようとしている。(著者抄録)

  • 胃癌por2の検出に有用な新しいモノクローナル抗体MUC1-014E(第3報) スキルス胃癌の壁深達度診断への応用

    米澤 傑, 北島 信一, 東 美智代, 堀之内 道子, 横山 勢也, 木村 伯子, 工藤 和洋, 下山 則彦, 清水 健, 後藤 正道

    日本病理学会会誌   103 ( 1 )   216 - 216   2014.3

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  • 特集「COPDを改めて問う」エピジェネティクスにおけるムチン発現制御. Reviewed

    米澤傑, 横山勢也 , 山田宗茂 , 北本祥, 東美智代

    THE LUNG perspectives   22 ( 2 )   77 - 82   2014

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    さまざまなヒト腫瘍において, MUC1 (汎上皮性膜結合ムチン)は予後不良因子であり, MUC2 (腸型分泌ムチン)は予後良好因子である. また, MUC4 (気管支型膜結合ムチン)高発現はさらなる予後不良に関連している. これらのムチンの遺伝子発現には, DNAメチル化とヒストン修飾というエピジェネティクスが関連している. われわれは, ヒトサンプルのような夾雑な検体の解析が可能な新規DNAメチル化解析法「methylation specific electrophoresis (MSE)」を開発し, 膵液内のMUC1・MUC2・MUC4をMSEで解析することにより, 高い感度と精度をもって, 診断の難しい膵腫瘍を早期に正確に診断するシステムを構築した. 現在, 肺癌におけるムチン発現の研究をベースとして, ヒト肺癌組織におけるMUC1とMUC4の「MSE」による解析が進んでおり, 喀痰や気管支肺胞洗浄液を用いて, ムチンのエピジェネティクスを応用した肺癌早期診断の扉が開かれようとしている.

  • 粘液産生性胆道系腫瘍の再出発―エビデンスとしての画像と病理 胆道系腫瘍における粘液産生の組織学的側面

    東美智代, 柴原弘明, 後藤優子, 平木翼, 横山勢也, 米澤傑

    胆とすい   34 ( 5 )   353 - 358   2013.5

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    J-GLOBAL

  • 特集:粘液産生性胆道系腫瘍の再出発-エビデンスとしての画像と病理 「胆道系腫瘍における粘液産生の組織学的側面」. Reviewed

    東美智代、 柴原弘明、後藤優子、平木 翼、横山勢也、米澤 傑

    胆と膵.   34 ( 5 )   353 - 358   2013.5

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  • 特集 胆膵病理II:胆膵共通のトピックス【胆膵共通疾患とトピックス】膵胆道腫瘍におけるMUC発現. Reviewed

    米澤 傑、東美智代、横山勢也、後藤優子、北島信一.

    病理と臨床.   31 ( 4 )   399 - 408   2013.4

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  • 浸潤性膵管癌におけるEUS-FNABでのムチン発現

    東 美智代, 横山 勢也, 後藤 優子, 平木 翼, 後藤 正道, 米澤 傑

    日本病理学会会誌   102 ( 1 )   320 - 320   2013.4

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  • 最も難治性である膵癌の早期質的診断ならびに進展度診断のシステム構築

    横山 勢也

    日本膵臓病研究財団研究報告書   19回   75 - 79   2012.12

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    CiNii Books

    Other Link: http://search.jamas.or.jp/link/ui/2015334661

  • 胆管内乳頭状腫瘍(IPNB):粘液,MUC発現からのアプローチ. Reviewed

    東美智代、横山勢也、北本 祥、米澤 傑.

    肝胆膵   65 ( 3 )   487 - 494   2012.9

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  • 癌におけるムチンの臨床病理学的意義および診断への応用 -難治性膵胆管癌の早期診断に向けて-. Reviewed

    米澤 傑、東美智代、横山勢也、北本 祥、山田宗茂.

    MEDICAL TECHNOLOGY   40 ( 4 )   419 - 425   2012.4

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  • 胃癌細胞(por2、sig)の検出に有用な新しいモノクローナル抗体「MUC1-014E」(第2報) 生検標本への応用

    米澤 傑, 北島 信一, 東 美智代, 堀之内 道子, 横山 勢也, 北本 祥, 田村 幸夫, 清水 健, 後藤 正道

    日本病理学会会誌   101 ( 1 )   262 - 262   2012.3

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  • 癌におけるムチンの臨床病理学的意義および診断への応用 −難治性膵胆管癌の早期診断に向けて−

    米澤傑, 東美智代, 横山勢也, 北本祥, 山田宗茂

    MEDICAL TECNOLOGY   40 ( 4 )   419 - 425   2012

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  • MUC17遺伝子のエピジェネティクス制御機構の解明

    北本 祥, 山田 宗茂, 横山 勢也, 北条 いづみ, 東 美智代, 後藤 正道, 米澤 傑

    日本病理学会会誌   100 ( 1 )   456 - 456   2011.3

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  • 見逃しやすい胃癌細胞(por2あるいはsig)を鮮明に検出できる新しいモノクローナル抗体「MUC1-O14E」

    米澤 傑, 北島 信一, 堀之内 道子, 清水 健, 田村 幸大, 後藤 正道, 横山 勢也, 東 美智代

    日本病理学会会誌   100 ( 1 )   304 - 304   2011.3

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  • Mucins in human neoplasms: Clinical pathology, gene expression and diagnostic application. Reviewed

    Yonezawa S, Higashi M, Yamada N, Yokoyama S, Kitamoto S, Kitajima S, Goto M

    Pathol Int   61 ( 12 )   697 - 716   2011

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  • 腫瘍発生と化生・粘液形質

    東美智代, 田畑和宏, 横山勢也, 山田宗茂, 米澤傑

    肝胆膵   62 ( 1 )   29 - 38   2011

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  • 分子マトリクス電気泳動(SMME)により分離したムチンの同定法の開発

    松野裕樹, 董偉傑, 横山勢也, 米澤傑, 成松久, 亀山昭彦

    生物物理化学(Web)   55 ( Suppl )   S40(J-STAGE)   2011

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    J-GLOBAL

  • 「第2部:病理診断医になじみのある疾患関連分子 MUC(腫瘍等)解説編・診断編」

    米澤傑, 山田宗茂, 横山勢也, 北本祥, 田畑和宏, 東美智代

    『病理と臨床(臨時増刊号)』文光堂   29   328 - 340   2011

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  • IPMNの組織亜型と分化発育. Reviewed

    米澤 傑、東美智代、山田宗茂、北本 祥、横山勢也、有坂好史、高折恭一.

    肝胆膵   61 ( 3 )   343 - 358   2010.9

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  • エピジェネティックによるMUC17遺伝子発現機構の解析(Expression of MUC17, a marker of pancreatic cancer, is under the control of epigenetic modifications)

    北本 祥, 山田 宗茂, 横山 勢也, 東 美智代, 後藤 正道, 米澤 傑

    日本癌学会総会記事   69回   339 - 339   2010.8

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  • MUC2 (mucin 2, oligomeric mucus/gel-forming) Reviewed

    Yonezawa S, Yamada N, Yokoyama S, Kitamoto S, Higashi M, Goto M

    Atlas of Genetics and Cytogenetics in Oncology and Haematology   2010

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  • 分子マトリクス電気泳動法を利用するバイオマーカー探索ストラテジーの構築

    松野裕樹、董偉傑、横山勢也、米澤傑、成松久、亀山昭彦

    生物物理化学   54   37   2010

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  • 腫瘍発生と化生・粘液形質 Reviewed

    東 美智代、田畑和宏、横山勢也、山田宗茂、米澤 傑

    肝胆膵   62 ( 1 )   29 - 38   2010

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  • 「IPMN の組織亜型と分化発育」

    米澤傑, 東美智代, 山田宗茂, 北本祥, 横山勢也, 有坂好史, 高折恭一

    肝胆膵、株式会社アークメディア   61 ( 3 )   343 - 358   2010

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  • MUC5AC遺伝子はプロモーター上流におけるDNAメチル化により制御されている(CpG methylation in the distal region of MUC5AC promoter contribute to the regulation of MUC5AC)

    山田 宗茂, 横山 勢也, 西田 ゆかり, 北条 いづみ, 堤田 英明, 後藤 正道, 東 美智代, 米澤 傑

    日本癌学会総会記事   68回   175 - 175   2009.8

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  • ヒト癌細胞株におけるMUC16遺伝子のエピジェネティクス解析(Epigenetic analysis of MUC16 in cancer cells)

    横山 勢也, 山田 宗茂, 北条 いづみ, 西田 ゆかり, 東 美智代, 後藤 正道, 米澤 傑

    日本癌学会総会記事   68回   175 - 175   2009.8

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  • MUC2 (mucin 2, oligomeric mucus/gel-forming) Reviewed

    Yonezawa S, Yamada N, Yokoyama S, Kitamoto S, Higashi M, Goto M

    Atlas of Genetics and Cytogenetics in Oncology and Haematology   14 ( 9 )   827 - 833   2009

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Presentations

  • 比嘉 那優大, 赤羽 俊章, 横山 勢也, 米澤 大, 内田 裕之, 浜田 大治, 霧島 茉莉, 谷本 昭英, 花谷 亮典, 吉本 幸司   IDH wild-type GBMにおけるPDGFRA amplificationおよびMGMTpの予後への影響  

    Brain Tumor Pathology  2022.5  日本脳腫瘍病理学会

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    Event date: 2022.5

    Language:Japanese  

  • 比嘉 那優大, 赤羽 俊章, 米澤 大, 内田 裕之, 藤尾 信吾, 横山 勢也, 霧島 茉莉, 濱田 大治, 谷本 昭英, 吉本 幸司   日本人のhigh grade glioma患者における遺伝子変異の特徴  

    Brain Tumor Pathology  2021.5  日本脳腫瘍病理学会

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    Event date: 2021.5

    Language:Japanese  

  • 米澤 大, 比嘉 那優大, 内田 裕之, 赤羽 俊章, 横山 勢也, 霧島 茉莉, 平木 翼, 谷本 昭英, 吉本 幸司   脳腫瘍に特化したがん遺伝子パネル検査の実臨床における有用性  

    Brain Tumor Pathology  2021.5  日本脳腫瘍病理学会

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    Event date: 2021.5

    Language:Japanese  

  • 比嘉那優大, 赤羽俊章, 米澤大, 内田裕之, 藤尾信吾, 横山勢也, 霧島茉莉, 浜田大治, 谷本昭英, 吉本幸司   悪性グリオーマのEGFR遺伝子変異とスプライシングバリアントの特徴  

    日本分子脳神経外科学会プログラム・抄録集  2021 

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    Event date: 2021

  • 比嘉 那優大, 赤羽 俊章, 横山 勢也, 米澤 大, 内田 裕之, 霧島 茉莉, 平木 翼, 谷本 昭英, 吉本 幸司   神経膠腫診断に特化した遺伝子パネルによるGlioblastoma、IDH-wildの解析結果  

    Brain Tumor Pathology  2020.8  日本脳腫瘍病理学会

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    Event date: 2020.8

    Language:Japanese  

  • 横山 勢也, 霧島 茉莉, 東 美智代, 谷本 昭英   胆管癌におけるDNAメチル化解析(DNA methylation analysis in bile duct)  

    日本病理学会会誌  2020.3  (一社)日本病理学会

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    Event date: 2020.3

    Language:English  

  • 東 美智代, 横山 勢也, 平木 翼, 北薗 育美, 霧島 茉莉, 田中 貴子, 濱田 一正, 堀之内 道子, 米澤 傑, 谷本 昭英   胆道・膵臓腫瘍の遺伝子異常と病理診断 胆道・膵腫瘍の早期診断とバイオマーカー  

    日本病理学会会誌  2020.3  (一社)日本病理学会

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    Event date: 2020.3

    Language:Japanese  

  • 比嘉那優大, 赤羽俊章, 横山勢也, 米澤大, 内田裕之, 霧島茉莉, 谷本昭英, 吉本幸司   Clinical and genetic features of distinct subgroup in TERT promoter wildtype-IDH wildtype glioblastomas  

    日本脳腫瘍学会プログラム・抄録集  2020 

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    Event date: 2020

  • 横山 勢也, 東 美智代, 谷本 昭英   DNAメチル化解析結果を用いた計算機科学による膵癌予後予測(Predicted Prognosis of Pancreatic Cancer Patients by Machine Learning)  

    日本癌学会総会記事  2019.9  (一社)日本癌学会

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    Event date: 2019.9

    Language:English  

  • 谷本 昭英, 赤羽 俊章, 西田 ゆかり, 横山 勢也, 平木 翼, 東 美智代, 鈴木 紳介, 上野 真一, 西原 広史   鹿児島大学がんゲノム医療への取り組み ヒトゲノム遺伝子解析センター(仮)の開設について  

    日本病理学会会誌  2019.4  (一社)日本病理学会

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    Event date: 2019.4

    Language:Japanese  

  • 横山 勢也, 東 美智代, 谷本 昭英   ムチン遺伝子のメチル化情報を用いた機械学習による膵癌摘出術後の予後評価(Prediction of prognosis with PDAC by Machine learning models using mucin genes methylation status)  

    日本病理学会会誌  2019.4  (一社)日本病理学会

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    Event date: 2019.4

    Language:English  

  • 横山 勢也, 東 美智代, 谷本 昭英   PDAC摘出術後におけるムチン遺伝子のメチル化解析を用いた予後予測法の構築(Construction of prognosis prediction for pancreatic ductal adenocarcinomas by methylation analysis of mucins promoters)  

    日本癌学会総会記事  2018.9  日本癌学会

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    Event date: 2018.9

    Language:English  

  • 横山 勢也, 東 美智代, 谷本 昭英   MUC1およびMUC4遺伝子のメチル化解析による膵癌摘出術後の予後評価(Aberrant methylation of MUC1 and MUC4 are potential risk marker for prognosis after surgery of PDAC)  

    日本病理学会会誌  2018.4  (一社)日本病理学会

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    Event date: 2018.4

    Language:English  

  • 横山 勢也, 東 美智代, 谷本 昭英   MUC1およびMUC4遺伝子のメチル化解析による膵癌摘出術後の予後評価(Aberrant methylation of MUC1 and MUC4 are potential risk marker for prognosis after surgery of PDAC)  

    日本病理学会会誌  2018.4  (一社)日本病理学会

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    Event date: 2018.4

    Language:English  

  • M. Higashi, S. Yokoyama, T. Hiraki, I. Kitazono, Y. Goto, M. Kirishima, S. Yamada, A. Tanimoto   Analysis of Mucin expression and DNA methylation in serous adenoma of the pancreas  

    VIRCHOWS ARCHIV  2017.9  SPRINGER

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    Event date: 2017.9

    Language:English  

  • Suguru Yonezawa, Seiya Yokoyama, Michiyo Higashi   Application of a novel DNA methylation analysis method (MSE) for mucin expression in pancreatic juices for diagnosis of pancreatic neoplasms  

    CANCER RESEARCH  2014.10  AMER ASSOC CANCER RESEARCH

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    Event date: 2014.10

    Language:English  

  • S. Yokoyama, S. Kitamoto, M. Higashi, H. Tsutsumida, J. Wakimoto, S. Yonezawa   TET1 was an important factor for DNA demethylation to regulate the expression of MUC1 and MUC4 in lung cancer  

    EUROPEAN JOURNAL OF CANCER  2014.7  ELSEVIER SCI LTD

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    Event date: 2014.7

    Language:English  

  • 東 美智代, 横山 勢也, 後藤 優子, 平木 翼, 後藤 正道, 米澤 傑   浸潤性膵管癌におけるEUS-FNABでのムチン発現  

    日本病理学会会誌  2013.4  (一社)日本病理学会

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    Event date: 2013.4

    Language:Japanese  

  • S. Yokoyama, S. Kitamoto, T. Hara, Y. Arisaka, K. Takaori, T. Yamamoto, T. Niihara, H. Nishimata, S. Tanaka, M. Higashi, S. Yonezawa   The Application of New DNA Methylation Analysis, Designated Methylation Specific Electrophoresis (MSE) for Pancreatic Juice Analysis  

    PANCREAS  2012.10  LIPPINCOTT WILLIAMS & WILKINS

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    Event date: 2012.10

    Language:English  

  • S. Kitamoto, M. Higashi, S. Yokoyama, S. Takao, S. Yonezawa   CTGF is Enhanced by Hypoxia Through Nuclear Recruitment of MUC1 in Pancreatic Cancer  

    EUROPEAN JOURNAL OF CANCER  2012.7  ELSEVIER SCI LTD

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    Event date: 2012.7

    Language:English  

  • M. Higashi, S. Kitamoto, S. Yokoyama, K. Tabata, S. Yonezawa   Immonohistochemical study of MUC17 expression in human pancreatic cancer  

    VIRCHOWS ARCHIV  2011.8  SPRINGER

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    Event date: 2011.8

    Language:English  

  • Sho Kitamoto, Norishige Yamada, Seiya Yokoyama, Izumi Houjou, Michiyo Higashi, Masamichi Goto, Surinder K. Batra, Suguru Yonezawa   Expression of MUC17, a marker of pancreatic cancer, is under the control of epigenetic modifications  

    CANCER RESEARCH  2011.4  AMER ASSOC CANCER RESEARCH

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    Event date: 2011.4

    Language:English  

  • 米澤 傑, 北島 信一, 堀之内 道子, 清水 健, 田村 幸大, 後藤 正道, 横山 勢也, 東 美智代   見逃しやすい胃癌細胞(por2あるいはsig)を鮮明に検出できる新しいモノクローナル抗体「MUC1-O14E」  

    日本病理学会会誌  2011.3  (一社)日本病理学会

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    Event date: 2011.3

    Language:Japanese  

  • 北本 祥, 山田 宗茂, 横山 勢也, 北条 いづみ, 東 美智代, 後藤 正道, 米澤 傑   MUC17遺伝子のエピジェネティクス制御機構の解明  

    日本病理学会会誌  2011.3  (一社)日本病理学会

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    Event date: 2011.3

    Language:Japanese  

  • 松野裕樹, 董偉傑, 横山勢也, 米澤傑, 成松久, 亀山昭彦   分子マトリクス電気泳動(SMME)により分離したムチンの同定法の開発  

    生物物理化学(Web)  2011 

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    Event date: 2011

    Language:Japanese  

  • 北本 祥, 山田 宗茂, 横山 勢也, 東 美智代, 後藤 正道, 米澤 傑   エピジェネティックによるMUC17遺伝子発現機構の解析(Expression of MUC17, a marker of pancreatic cancer, is under the control of epigenetic modifications)  

    日本癌学会総会記事  2010.8  日本癌学会

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    Event date: 2010.8

    Language:English  

  • 松野裕樹, 董偉傑, 横山勢也, 米澤傑, 成松久, 亀山昭彦   分子マトリクス電気泳動法を利用するバイオマーカー探索ストラテジーの構築  

    生物物理化学(Web)  2010 

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    Event date: 2010

    Language:Japanese  

  • 山田 宗茂, 横山 勢也, 西田 ゆかり, 北条 いづみ, 堤田 英明, 後藤 正道, 東 美智代, 米澤 傑   MUC5AC遺伝子はプロモーター上流におけるDNAメチル化により制御されている(CpG methylation in the distal region of MUC5AC promoter contribute to the regulation of MUC5AC)  

    日本癌学会総会記事  2009.8  日本癌学会

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    Event date: 2009.8

    Language:English  

  • 横山 勢也, 山田 宗茂, 北条 いづみ, 西田 ゆかり, 東 美智代, 後藤 正道, 米澤 傑   ヒト癌細胞株におけるMUC16遺伝子のエピジェネティクス解析(Epigenetic analysis of MUC16 in cancer cells)  

    日本癌学会総会記事  2009.8  日本癌学会

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    Event date: 2009.8

    Language:English  

  • 平木 翼, 北薗 育美, 後藤 優子, 田崎 貴嗣, 霧島 茉莉, 横山 勢也, 東 美智代, 畑中 一仁, 谷本 昭英   胆嚢癌におけるムチン発現の検討と予後との関連(Analysis of the relation between mucin expression and prognosis of gallbladder carcinoma)  

    日本病理学会会誌  2016.4 

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  • 米澤 傑, 北島 信一, 東 美智代, 堀之内 道子, 横山 勢也, 木村 伯子, 工藤 和洋, 下山 則彦, 清水 健, 後藤 正道   胃癌por2の検出に有用な新しいモノクローナル抗体MUC1-014E(第3報) スキルス胃癌の壁深達度診断への応用  

    日本病理学会会誌  2014.3 

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  • 米澤傑, 北島信一, 東美智代, 堀之内道子, 横山勢也, 木村伯子, 工藤和洋, 下山則彦, 清水健, 後藤正道   胃癌por2の検出に有用な新いモノクローナル抗体MUC1‐014E(第3報):スキルス胃癌の壁深達度診断への応用  

    日本病理学会会誌  2014.3 

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  • 横山 勢也, 北本 祥, 堤田 英明, 東 美智代, 米澤 傑   肺癌におけるMUC1遺伝子のメチル化ステータスとmRNA発現解析(DNA promoter methylation status and mRNA expression status of MUC1 in lung cancer)  

    日本癌学会総会記事  2013.10 

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  • 東美智代, 横山勢也, 前村公成, 蔵原弘, 又木雄弘, 後藤優子, 北薗育美, 平木翼, 畑中一仁, 谷本昭英   浸潤性膵管癌におけるムチン遺伝子のDNAメチル化状況の解析~新規解析法(MSE法)を用いて  

    日本消化器癌発生学会総会プログラム・抄録集  2016 

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  • 米澤 傑, 横山 勢也, 東 美智代   新しい高感度DNAメチル化検出法「MSE」を用いた膵液解析による膵腫瘍の診断(Diagnosis of pancreatic neoplasms by a novel high sensitive DNA methylation analysis method "MSE" for pancreatic juices)  

    日本癌学会総会記事  2013.10 

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  • 永田宏次, 神谷知貴, 横山勢也, 南雄二, 田之倉優   ソテツ由来抗菌ペプチドCy‐AMP1のX線結晶構造解析  

    日本蛋白質科学会年会プログラム・要旨集  2016.5 

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  • 永田宏次, 神谷知貴, 横山勢也, 南雄二, 田之倉優   ソテツ由来抗菌ペプチドCy‐AMP1のX線結晶構造解析  

    日本農芸化学会大会講演要旨集(Web)  2016.3 

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  • 東 美智代, 横山 勢也, 平木 翼, 北薗 育美, 後藤 優子, 田崎 貴嗣, 霧島 茉莉, 畑中 一仁, 谷本 昭英   膵漿液性腫瘍におけるムチン発現とDNAメチル化の解析(Analysis of Mucin expression and DNA methylation in serous adenoma of the pancreas)  

    日本病理学会会誌  2016.4 

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    Language:English  

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Intellectual Property

  • 予後推定装置、情報取得方法、プログラム及び胆道癌の予後推定用キット

    横山勢也, 東美智代, 谷本昭英

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    Application no:特願2022-007920  Date applied:2022

  • 癌の判定装置、癌の情報取得方法及びプログラム

    横山勢也, 東美智代, 谷本昭英

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    Application no:特願2022-160396  Date applied:2022

  • DISCRIMINATION METHOD OF PROGNOSTIC RISK AFTER PANCREATIC TUMOR EXTRACTION OPERATION

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    Applicant:Kagoshima university

    Application no:特願2018-111885  Date applied:2018.6

    Announcement no:特開2019-213473  Date announced:2019.12

  • 膵腫瘍の病型診断方法

    横山 勢也, 米澤 傑, 北本 祥

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    Applicant:国立大学法人 鹿児島大学

    Application no:特願2013-523061  Date applied:2012.6

    Patent/Registration no:特許第5866739号  Date issued:2016.1

    J-GLOBAL

  • 新規なDNAメチル化解析方法

    横山 勢也, 米澤 傑

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    Applicant:国立大学法人 鹿児島大学

    Application no:JP2011060339  Date applied:2011.4

    Announcement no:WO2011-132798  Date announced:2011.10

    J-GLOBAL

Awards

  • 鹿児島テックプランター・特別賞

    2022.2   リバネス   革新的スクリーニング技術による膵臓癌の克服に向けて

    Seiya Yokoyama

  • 優秀研究論文顕彰

    2021.2   A Grant from the Kodama Memorial Fund for Medical Research  

    Seiya Yokoyama

  • 膵臓病研究奨励賞

    2018.12   公益財団法人日本膵臓病研究財団  

    横山 勢也

  • Young Investigator Award

    2012.10   International Symposium on Pancreatic Cancer  

    Seiya Yokoyama

Research Projects

  • Construction of DNA Methylation Markers for liqid biopsy of Pancreatic Cancer.

    Grant number:21K07222  2021.4 - 2024.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

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    Grant amount:\4160000 ( Direct Cost: \3200000 、 Indirect Cost:\960000 )

  • 膵癌摘出術後リスク判別法における適応可能な検体スペクトルの検討

    Grant number:A239  2021.4

    Japan Agency for Medical Research and Development  橋渡し研究プログラム・シーズA 

    Seiya Yokoyama

  • A fundamental study for construction of bile duct cancer early diagnosis method by DNA methylation analysis.

    Grant number:18K07326  2018.4 - 2021.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)  Grant-in-Aid for Scientific Research (C)

    Yokoyama Seiya

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    Grant amount:\4550000 ( Direct Cost: \3500000 、 Indirect Cost:\1050000 )

    Cholangiocarcinoma is one of the most intractable cancers among all cancers, and it is difficult to diagnose at a stage where early detection as well as cure can be expected. Therefore, it is desirable to establish an early diagnosis method for cholangiocarcinoma and a method to determine the malignancy of mucous-producing cholangiocarcinoma and mucinous cystic cholangiocarcinoma, which have been attracting attention recently. In this project, we constructed a Bisulfite Amplicon Sequencing (BSAS) panel for DNA methylation analysis of 14 cancer-related genes including mucin genes related to the malignancy of cholangiocarcinoma. Then we analyzed the methylation of tumor and non-tumor portions of cholangiocarcinoma tissue specimens (125 cases: 250 specimens including non-neoplastic region and neoplastic region) used this panel. In addition, to evaluated the BSAS panel analysis for clinical application, we compared analysis data with clinical information.

  • A fundamental study for construction of PDAC early diagnosis method by DNA methylation analysis.

    Grant number:15K21247  2015.4 - 2018.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    Yokoyama Seiya

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    Grant amount:\4030000 ( Direct Cost: \3100000 、 Indirect Cost:\930000 )

    Pancreatic ductal adenocarcinoma (PDAC) has high frequency of recurrence even if possible to surgery. In this program, we analyzed DNA methylation status of mucin genes using pancreatic tissue with/without tumor to construct marker for predicting prognosis after surgery. The methylation status of MUC1 and MUC4 are statistically associated with clinicopathological information. Our result suggested that MUC1 and MUC4 methylation status has potential for predicted prognosis.

  • Basic research for early diagnosis of lung carcinomas by the application of DNA methylation analysis

    Grant number:24701008  2012.4 - 2014.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)  Grant-in-Aid for Young Scientists (B)

    YOKOYAMA Seiya

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    Grant amount:\4420000 ( Direct Cost: \3400000 、 Indirect Cost:\1020000 )

    Lung cancer is still a disease of high mortality, despite advanced diagnostic techniques. Mucins (MUC) play crucial roles in carcinogenesis and tumor invasion in lung neoplasms. We have developed a novel 'methylation-specific electrophoresis (MSE)' method to analyze the DNA methylation status of MUC1 and MUC4 by high sensitivity and resolution.
    By using the MSE method, we evaluated lung tissue samples from 33 patients with various lung lesions. Our results showed that the TET1 was important factor for DNA demethylation to regulate the expression of MUC1 and MUC4 in lung cancer. The analysis of the epigenetic changes of MUC1 and MUC4 may be useful for diagnosing the carcinogenic risk and predicting outcome of patients.

  • ムチン発現解析を応用した胆管癌の早期診断法の開発

    2012.4

    Japan Science and Technology Agency  A-STEP 

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    Authorship:Principal investigator 

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