Investigation of the role of BRG1 in acinar cell-derived pancreatic tumorigenesis

• Project/Area Number: 17H06805
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Gastroenterology
• Research Institution: Kyoto University
• Principal Investigator: Tsuda Motoyuki 京都大学, 医学研究科, 医員 (30802764)
• Project Period (FY): 2017-08-25 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 膵癌 / エピジェネティクス / SWI/SNF / BRG1 / クロマチンリモデリング / 医学 / 消化器内科学 / マウス

Outline of Final Research Achievements

BRG1, a core subunit of SWI/SNF chromatin remodeling complex, is silenced in approximately 10% of human pancreatic ductal adenocarcinoma (PDA). We previously showed that BRG1 inhibits the formation of intraductal pancreatic mucinous neoplasm (IPMN) and that IPMN-derived PDA originated from ductal cells. However, the role of BRG1 in pancreatic intraepithelial neoplasia-derived (PanIN-derived) PDA that originated from acinar cells remains elusive. Here, we found that exclusive elimination of Brg1 in acinar cells impaired the formation of PanIN in mice. Brg1 directly regulated SOX9 expression and SOX9 overexpression canceled this PanIN-attenuated phenotype. Furthermore, Brg1 deletion in established PanIN resulted in regression of PanIN in mice. Finally, BRG1 expression correlated with SOX9 expression in human PDA. In summary, BRG1 is critical for PanIN initiation and progression through positive regulation of SOX9. Thus, the BRG1/SOX9 axis is a potential target for PanIN-derived PDA.

Academic Significance and Societal Importance of the Research Achievements

膵癌は最難治癌であり、新規治療標的の探索が望まれている。BRG1は膵癌の14%で変異を認めるSWI/SNF複合体の中心分子で、膵癌の10%程度で発現消失している。我々は以前にBRG1の欠失により膵管細胞から予後良好な前癌病変IPMNが形成され膵癌に至ることを報告したが、膵癌の大多数を占め、より予後不良な膵癌に至るPanINにおけるBRG1の役割は不明であった。
本研究により、IPMNとは逆に、より予後不良な膵癌に至るPanINの形成・維持においてBRG1が必要であることが明らかになり、今後膵癌におけるBRG1やSOX9をターゲットとした創薬の検討につながる重要な結果であると考える。

Research Products

• [Int'l Joint Research] UCSF/Vanderbilt University(米国)
• [Int'l Joint Research] Technische Universitat Munchen(ドイツ)
• [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
• [Presentation] The BRG1/SOX9 axis plays a critical role for acinar cell-derived pancreatic tumorigenesis (2018)
  • Author(s): Motoyuki Tsuda, Akihisa Fukuda, Hiroshi Seno
  • Organizer: AACR meeting:Pancreatic Cancer: Advances in Science and Clinical Care
  • Int'l Joint Research
• [Presentation] Brg1はPanINの維持・PanIN由来膵癌の形成にapoptosisの制御を介し重要な役割を果たす (2018)
  • Author(s): 津田喬之、福田晃久、妹尾浩
  • Organizer: 第49回日本膵臓学会大会
• [Presentation] BRG1/SOX9 axis is critical for acinar cell-derived pancreatic tumorigenesis (2018)
  • Author(s): Motoyuki Tsuda, Akihisa Fukuda, Hiroshi Seno
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] BRG1 is indispensable for acinar cell-derived pancreatic tumorigenesis through controlling SOX9 expression (2017)
  • Author(s): 津田 喬之
  • Organizer: 第47回日本癌学会総会
• [Presentation] BRG1はSox9の発現制御を介しPanINの形成・維持に重要な役割をはたす (2017)
  • Author(s): 津田 喬之
  • Organizer: JDDW2018