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Identification of factors contributing to epigenetic alteration and maintenance in EBV infection.

Research Project

Project/Area Number 16K08729
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Experimental pathology
Research InstitutionChiba University

Principal Investigator

Matsusaka Keisuke  千葉大学, 大学院医学研究院, 講師 (40610150)

Research Collaborator FUKUYO Masaki  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
KeywordsDNAメチル化 / Epstein-Barr virus / 胃癌 / エピジェネティクス / ウイルス / EBV
Outline of Final Research Achievements

We demonstrated that Epstein-Barr virus (EBV) infection induced de novo DNA methylation in immortalized normal gastric epithelial cell, GES1, as well as gastric cancer cell, MKN7. Post-infection time-series DNA methylation analyses showed that EBV infection exerted strong pressure to induce de novo DNA methylation in gastric epithelial cells within a month in a spatiotemporally well-ordered manner. RNA-seq analysis showed that multiple EBV genes expression in early infection phase, indicating that complicated mechanisms should be involved in de novo DNA methylation induction. We established effective EBV dropout system using mutant EBNA1 labeled by fluorescent protein.

Academic Significance and Societal Importance of the Research Achievements

EBV関連腫瘍は、高齢化社会や高度先進医療に伴った免疫抑制状態で今後増加することが予想され、その対策は喫緊の課題である。本研究によりEBV感染がEBV陽性胃癌の際だったエピゲノム異常の原因であることが示され、その発がん機構にエピゲノム異常が重要であることが示された。また、EBV感染を効率的に脱落させられる系が確立し、EBVと宿主との相互作用に影響を及ぼす新規治療戦略の可能性が示された。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (20 results)

All 2018 2017 2016 Other

All Journal Article (10 results) (of which Peer Reviewed: 10 results,  Open Access: 9 results) Presentation (7 results) Book (2 results) Remarks (1 results)

  • [Journal Article] The frequency of promoter DNA hypermethylation is decreased in colorectal neoplasms of familial adenomatous polyposis.2018

    • Author(s)
      Takane K, Fukuyo M, Matsusaka K, Ota S, Rahmutulla B, Matsushita K, Miyauchi H, Nakatani Y, Matsubara H, Kaneda A.
    • Journal Title

      Oncotarget.

      Volume: 9 Issue: 66 Pages: 32653-32666

    • DOI

      10.18632/oncotarget.25987

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Synergistic Cytotoxic Effect on Gastric Cancer Cells of an Immunotoxin Cocktail in Which Antibodies Recognize Different Epitopes on CDH172018

    • Author(s)
      Kusano-Arai O, Iwanari H, Kudo S, Akiba H, Matsusaka K, Kaneda A, Fukayama M, Tsumoto K, Hamakubo T.
    • Journal Title

      Monoclonal Antibodies in Immunodiagnosis and Immunotherapy

      Volume: 37 Issue: 1 Pages: 1-11

    • DOI

      10.1089/mab.2017.0043

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Epstein-Barr virus infection induces genome-wide de novo DNA methylation in non-neoplastic gastric epithelial cells.2017

    • Author(s)
      Matsusaka K, Funata S, Fukuyo M, Seto Y, Aburatani H, Fukayama M, Kaneda A.
    • Journal Title

      Journal of Pathology

      Volume: 242 Issue: 4 Pages: 391-399

    • DOI

      10.1002/path.4909

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Frequent promoter hypermethylation associated with human papillomavirus infection in pharyngeal cancer.2017

    • Author(s)
      Nakagawa T, Matsusaka K, Misawa K, Ota S, Takane K, Fukuyo M, Rahmutulla B, Shinohara K, Kunii N, Sakurai D, Hanazawa T, Matsubara H, Nakatani Y, Okamoto Y, Kaneda A.
    • Journal Title

      Cancer Letters

      Volume: 407 Pages: 21-31

    • DOI

      10.1016/j.canlet.2017.08.008

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Regulation of tumour related genes by dynamic epigenetic alteration at enhancer regions in gastric epithelial cells infected by Epstein-Barr virus.2017

    • Author(s)
      Okabe A, Funata S, Matsusaka K, Namba H, Fukuyo M, Rahmutulla B, Oshima M, Iwama A, Fukayama M, Kaneda A.
    • Journal Title

      Scientific reports

      Volume: 7 Issue: 1 Pages: 7924-7924

    • DOI

      10.1038/s41598-017-08370-7

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] A. Histone modification alteration coordinated with acquisition of promoter DNA methylation during Epstein-Barr virus infection.2017

    • Author(s)
      Funata S, Matsusaka K, Yamanaka R, Yamamoto S, Okabe A, Fukuyo M, Aburatani H, Fukayama M, Kaneda A.
    • Journal Title

      Oncotarget

      Volume: 8 Issue: 33 Pages: 55265-55279

    • DOI

      10.18632/oncotarget.19423

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Tumor Content Chart-Assisted HER2/CEP17 Digital PCR Analysis of Gastric Cancer Biopsy Specimens.2016

    • Author(s)
      Matsusaka K, Ishikawa S, Nakayama A, Ushiku T, Nishimoto A, Urabe M, Kaneko N, Kunita A, Kaneda A, Aburatani H, Fujishiro M, Seto Y, Fukayama M.
    • Journal Title

      PLoS One

      Volume: 11 Issue: 4 Pages: e0154430-e0154430

    • DOI

      10.1371/journal.pone.0154430

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Coupling CDH17 and CLDN18 markers for comprehensive membrane-targeted detection of human gastric cancer.2016

    • Author(s)
      Matsusaka K, Ushiku T, Urabe M, Fukuyo M, Abe H, Ishikawa S, Seto Y, Aburatani H, Hamakubo T, Kaneda A, Fukayama M.
    • Journal Title

      Oncotarget

      Volume: 7 Issue: 51 Pages: 64168-64181

    • DOI

      10.18632/oncotarget.11510

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Coupling CDH17 and CLDN18 markers for comprehensive membrane-targeted detection of human gastric cancer.2016

    • Author(s)
      K. Matsusaka, T. Ushiku, M. Urabe, M. Fukuyo, H. Abe, S. Ishikawa, Y. Seto, H. Aburatani, T. Hamakubo, A. Kaneda, M. Fukayama
    • Journal Title

      Oncotarget

      Volume: 7 Issue: 39 Pages: 64168-64181

    • DOI

      10.18632/oncotarget.11638

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] TET2 functions as a resistance factor against DNA methylation acquisition during Epstein-Barr virus infection.2016

    • Author(s)
      Namba-Fukuyo H, Funata S, Matsusaka K, Fukuyo M, Rahmutulla B, Mano Y, Fukayama M, Aburatani H, Kaneda A
    • Journal Title

      Oncotarget

      Volume: 7 Issue: 49 Pages: 81512-81526

    • DOI

      10.18632/oncotarget.13130

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 胃癌におけるTP53変異とは独立したゲノム・エピゲノム相互作用の同定2018

    • Author(s)
      松坂恵介, 眞野恭伸, 福世真樹, 浦辺雅之, 喜多和子, 根本哲宏, バハテヤリ・ラムヒトラ, 瀬戸泰之, 深山正久, 金田篤志.
    • Organizer
      第107回日本病理学会総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Identification of genetic/epigenetic alterations based on wild-type TP53 in high methylation gastric cancer.2018

    • Author(s)
      Keisuke Matsusaka, Yasunobu Mano, Masaki Fukuyo, Masayuki Urabe, Rahmutulla Bahityar, Eriko Ikeda, Kazuko Kita, Hiroyuki Abe, Tetsuhiro Nemoto, Yasuyuki Seto, Masashi Fukayama, Atsushi Kaneda.
    • Organizer
      The 77th Annual Meeting of the Japanese Cancer Association
    • Related Report
      2018 Annual Research Report
  • [Presentation] 高メチル化胃癌におけるTP53変異非依存性ゲノム・エピゲノム異常の相乗効果.2018

    • Author(s)
      松坂恵介、眞野恭伸、福世真樹、松田和暁、井上貴登、浦辺雅之、バハテヤリ・ラヒムトラ、池田英里子、阿部浩幸、喜多和子、瀬戸泰之、根本哲宏、深山正久、金田篤志.
    • Organizer
      第29回日本消化器癌発生学会総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] メチル化胃癌における特異的なゲノム・エピゲノム変異の同定2017

    • Author(s)
      松坂恵介、眞野恭伸、福世真樹、浦辺雅之、油谷浩幸、深山正久、瀬戸泰之、金田篤志.
    • Organizer
      第76回日本癌学会総会
    • Related Report
      2017 Research-status Report
  • [Presentation] Identification of unique genetic/epigenetic alteration in gastric cancer with high DNA methylation.2017

    • Author(s)
      松坂恵介, 眞野恭伸、福世真樹、浦辺雅之、バハテヤリ・ラムヒトラ、油谷浩幸、瀬戸泰之、深山正久、金田篤志
    • Organizer
      第106回日本病理学会学術総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 発がんに関わるエピゲノム異常誘導因子としての病原体の意義2016

    • Author(s)
      松坂恵介
    • Organizer
      日本環境変異原学会 第45回大会
    • Place of Presentation
      つくば国際会議場(茨城県、つくば市)
    • Year and Date
      2016-11-17
    • Related Report
      2016 Research-status Report
  • [Presentation] Unique genetic and epigenetic features of gastric cancer subtypes with high-methylation or Epstein-Barr virus infection2016

    • Author(s)
      Matsusaka K, Mano Y, Fukuyo M, Urabe M, Rahmutulla B, Sakai E, Aburatani H, Seto Y, Fukayama M, Kaneda A.
    • Organizer
      The75th Annual Meeting of the Japanese Cancer Association
    • Place of Presentation
      パシフィコ横浜(神奈川県、横浜市)
    • Year and Date
      2016-10-06
    • Related Report
      2016 Research-status Report
  • [Book] DNA and Histone Methylation as Cancer Targets2017

    • Author(s)
      Matsusaka K, Kaneda A.
    • Total Pages
      624
    • Publisher
      Springer
    • ISBN
      9783319597867
    • Related Report
      2017 Research-status Report
  • [Book] 病理と臨床2016

    • Author(s)
      松坂恵介、宇於崎宏
    • Total Pages
      4
    • Publisher
      文光堂
    • Related Report
      2016 Research-status Report
  • [Remarks] 千葉大学大学院医学研究院分子腫瘍学

    • URL

      http://www.m.chiba-u.ac.jp/class/moloncol/

    • Related Report
      2018 Annual Research Report 2017 Research-status Report 2016 Research-status Report

URL: 

Published: 2016-04-21   Modified: 2020-03-30  

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