The functional role of chromatin remodeling regualtor Arid11a in pancreatic cancer

• Project/Area Number: 16K09394
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kyoto University
• Principal Investigator: Fukuda Akihisa 京都大学, 医学研究科, 特定病院助教 (70644897)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); 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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 膵がん / IPMN / エピゲネティクス / クロマチンリモデリング / マウスモデル / 膵癌 / エピジェネティクス / 起源細胞 / マウス / 胆道学 / 膵臓学

Outline of Final Research Achievements

Arid1a inhibits duct cell-derived IPMN and subsequent formation of pancreatic ductal adenocarcinoma (PDAC) in the context of oncogenic Kras, demonstrating a tumor-suppressive role of Arid1a in the pancreas in vivo. Arid1a prevents the dedifferentiation of pancreatic ductal cells and maintains pancreatic ductal structure in part through regulation of Sox9 expression, providing mechanistic insight into IPMN formation. Expression of ARID1A and SOX9/components of the mTOR pathway was positively correlated in human IPMN and PDCA. Our data point to Arid1a as a cell-type specific mediator of Kras-driven tumorigenesis in the pancreas and underscore that the SWI/SNF chromatin remodeling complex is a critical determinant for the distinct route of PDAC formation. Yoshito Kimura, Akihisa Fukuda, et al. Gastroenterology 2018:155:194-209.

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Academic Significance and Societal Importance of the Research Achievements

エピジェネティックな遺伝子発現制御に重要な働きをするSWI/SNFクロマチンリモデリング複合体のサブユニットArid1aの欠失によって、膵管細胞が脱分化して可塑性を獲得し、IPMNおよびIPMN由来膵癌が生じることをマウスの個体レベルで初めて明らかにした。これは近年ヒトIPMNで報告されたGNASやRNF43の遺伝子異常とは異なるIPMN経由の膵発癌ルートであり、これらのIPMNおよびIPMN由来膵癌の新規遺伝子改変マウスモデルは、今後のIPMNおよびIPMN由来膵癌の研究における有力なツールになり得ると考えられる。

Research Products

• [Journal Article] ARID1A Maintains Differentiation of Pancreatic Ductal Cells and inhibits Development of Pancreatic Ductal Adenocarcinoma in Mice (2018)
  • Author(s): Yoshito Kimura, Akihisa Fukuda, Satoshi Ogawa, Takahisa Maruno, Yutaka Takada, Motoyuki Tsuda, Yukiko Hiramatsu, Osamu Araki, Munemasa Nagao, Takaaki Yoshikawa, Kozo Ikuta, Takuto Yoshioka, Zong Wang, Haruhiko Akiyama, Christopher V. Wright, Kyoichi Takaori, Shinji Uemoto, Tsutomu Chiba, Hiroshi Seno
  • Journal Title: Gastroenterology Volume: 3 Issue: 1 Pages: 30346-9
  • DOI: 10.1053/j.gastro.2018.03.039
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The BRG1/SOX9 axis is critical for acinar cell-derived pancreatic tumorigenesis. (2018)
  • Author(s): Tsuda M, Fukuda A, Roy N, Hiramatsu Y, Leonhardt L, Kakiuchi N, Hoyer K, Ogawa S, Goto N, Ikuta K, Kimura Y, Matsumoto Y, Takada Y, Yoshioka T, Maruno T, Yamaga Y, Kim GE, Akiyama H, Ogawa S, Wright CV, Saur D, Takaori K, Uemoto S, Hebrok M, Chiba T, Seno H.
  • Journal Title: J Clin Invest. Volume: 128 Issue: 8 Pages: 3475-3489
  • DOI: 10.1172/jci94287
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nardilysin inhibits pancreatitis and suppresses pancreatic ductal adenocarcinoma initiation in mice. (2018)
  • Author(s): Ikuta K, Fukuda A, Ogawa S, Masuo K, Goto N, Hiramatsu Y, Tsuda M, Kimura Y, Matsumoto Y, Kimura Y, Maruno T, Kanda K, Nishi K, Takaori K, Uemoto S, Takaishi S, Chiba T, Nishi E, Seno H.
  • Journal Title: Gut Volume: 印刷中 Issue: 5 Pages: 882-892
  • DOI: 10.1136/gutjnl-2017-315425
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Brg1 plays an essential role in development and homeostasis of the duodenum through regulation of Notch signaling (2016)
  • Author(s): Takada Y, Fukuda A, Chiba T, Seno H.
  • Journal Title: Development Volume: 143 Issue: 19 Pages: 3532-3539
  • DOI: 10.1242/dev.141549
  • Peer Reviewed / Open Access