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

2018 Fiscal Year Final Research Report

• 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
• Keywords: 膵癌 / エピジェネティクス / SWI/SNF / BRG1

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.

Free Research Field

消化器内科学

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。