Analysis of histone modification system that governs the progression of pancreatic oncogenesis

• Project/Area Number: 16K09390
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo
• Principal Investigator: TATEISHI KEISUKE 東京大学, 医学部附属病院, 講師 (20396948)
• Co-Investigator(Kenkyū-buntansha): 中井 陽介 東京大学, 医学部附属病院, 准教授 (80466755) ; 水野 卓 東京大学, 医学部附属病院, 助教 (30771050)
• 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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 膵癌 / 膵がん / エピジェネテイクス / エピゲノム / クロマチン / ヒストン

Outline of Final Research Achievements

In this research, we sought to unravel the significance of epigenetics regulation in pancreas carcinogenesis. The pancreas- specific KrasG12D mice spontaneously developing pancreatic neoplasms were crossed with the EHMT deficient mice. EHMT deficiency suppressed the malignant progression of pancreatic precancerous lesions under Kras activation, suggesting the significance of histone modification processes regulated by EHMT in pancreatic oncogenesis. In addition, we analyzed the genes responsible for the protumorigenic effects of Ehmt.

Academic Significance and Societal Importance of the Research Achievements

膵癌においては代表的な４つの遺伝子変異がよく知られているが、それらの存在のみが膵前癌病変の進行に必要十分であるとはいえない。エピジェネテイクス修飾は遺伝子発現を調節する機構であり、癌における重要性も明らかになりつつあることから、それらを標的として制御する薬剤も開発されつつある。本研究において膵癌の発生進行に関わるエピジェネテイクス修飾機構が明らかにされ、その意義が解明されることによる臨床的有用性は高いと考えられる。

Research Products

• [Journal Article] Blocking CXCLs?CXCR2 axis in tumor?stromal interactions contributes to survival in a mouse model of pancreatic ductal adenocarcinoma through reduced cell invasion/migration and a shift of immune-inflammatory microenvironment (2019)
  • Author(s): Sano Makoto、Ijichi Hideaki、Takahashi Ryota、Miyabayashi Koji、Fujiwara Hiroaki、Yamada Tomoharu、Kato Hiroyuki、Nakatsuka Takuma、Tanaka Yasuo、Tateishi Keisuke、Morishita Yasuyuki、Moses Harold L.、Isayama Hiroyuki、Koike Kazuhiko
  • Journal Title: Oncogenesis Volume: 8 Issue: 2 Pages: 8-8
  • DOI: 10.1038/s41389-018-0117-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Isocitrate dehydrogenase 1 mutation sensitizes intrahepatic cholangiocarcinoma to the BET inhibitor JQ1 (2018)
  • Author(s): Fujiwara Hiroaki、Tateishi Keisuke、Kato Hiroyuki、Nakatsuka Takuma、Yamamoto Keisuke、Tanaka Yasuo、Ijichi Hideaki、Takahara Naminatsu、Mizuno Suguru、Kogure Hirofumi、Matsubara Saburo、Nakai Yousuke、Koike Kazuhiko
  • Journal Title: Cancer Science Volume: 109 Issue: 11 Pages: 3602-3610
  • DOI: 10.1111/cas.13784
  • Peer Reviewed
• [Journal Article] A phase II trial of gemcitabine, S-1 and LV combination (GSL) therapy in patients with advanced pancreatic cancer (2018)
  • Author(s): Saito K、Isayama H、Nakai Y、Takahara N、Ishigaki K、Takeda T、Hakuta R、Saito T、Uchino R、Kishikawa T、Hamada T、Mizuno S、Sasaki T、Kogure H、Matsubara S、Yamamoto N、Ijichi H、Tateishi K、Tada M、Koike K
  • Journal Title: Investigational New Drugs Volume: 37 Issue: 2 Pages: 338-344
  • DOI: 10.1007/s10637-018-0691-9
  • Peer Reviewed
• [Journal Article] A phase II trial of gemcitabine, S-1 and LV combination (GSL) neoadjuvant chemotherapy for patients with borderline resectable and locally advanced pancreatic cancer (2018)
  • Author(s): Saito Kei、Isayama Hiroyuki、Sakamoto Yoshihiro、Nakai Yousuke、Ishigaki Kazunaga、Tanaka Mariko、Watadani Takeyuki、Arita Junichi、Takahara Naminatsu、Mizuno Suguru、Kogure Hirofumi、Ijichi Hideaki、Tateishi Keisuke、Tada Minoru、Hasegawa Kiyoshi、Fukayama Masashi、Kokudo Norihiro、Koike Kazuhiko
  • Journal Title: Medical Oncology Volume: 35 Issue: 7 Pages: 100-100
  • DOI: 10.1007/s12032-018-1158-8
  • Peer Reviewed
• [Journal Article] Prevalence of Pancreatic Cystic Lesions Is Associated With Diabetes Mellitus and Obesity: An Analysis of 5296 Individuals Who Underwent a Preventive Medical Examination. (2017)
  • Author(s): Mizuno S, Isayama H, Nakai Y, Yoshikawa T, Ishigaki K, Matsubara S, Yamamoto N, Ijichi H, Tateishi K, Tada M, Hayashi N, Koike K.
  • Journal Title: Pancreas Volume: 46 Issue: 6 Pages: 801-805
  • DOI: 10.1097/mpa.0000000000000833
  • Peer Reviewed
• [Journal Article] Epigenome modifying enzymes regulate development and progression of pancreatic cancers (2016)
  • Author(s): 立石敬介, 山本恵介, 小池和彦
  • Journal Title: Suizo Volume: 31 Issue: 1 Pages: 69-75
  • DOI: 10.2958/suizo.31.69
  • NAID: 130005137839
  • ISSN: 0913-0071, 1881-2805
  • Peer Reviewed