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

• Project/Area Number: 16K08729
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Chiba 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: ¥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)
• Keywords: DNA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。

Research Products

• [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
  • Peer Reviewed / Open Access
• [Journal Article] Synergistic Cytotoxic Effect on Gastric Cancer Cells of an Immunotoxin Cocktail in Which Antibodies Recognize Different Epitopes on CDH17 (2018)
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
• [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
• [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
• [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
• [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
• [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
• [Presentation] Unique genetic and epigenetic features of gastric cancer subtypes with high-methylation or Epstein-Barr virus infection (2016)
  • 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
• [Book] DNA and Histone Methylation as Cancer Targets (2017)
  • Author(s): Matsusaka K, Kaneda A.
  • Total Pages: 624
  • Publisher: Springer
  • ISBN: 9783319597867
• [Book] 病理と臨床 (2016)
  • Author(s): 松坂恵介、宇於崎宏
  • Total Pages: 4
  • Publisher: 文光堂
• [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/