2018 Fiscal Year Final Research Report
The functional role of chromatin remodeling regualtor Arid11a in pancreatic cancer
| Project/Area Number |
16K09394
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Kyoto University |
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Principal Investigator |
Fukuda Akihisa 京都大学, 医学研究科, 特定病院助教 (70644897)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| 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 |
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| 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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| Free Research Field |
膵がん
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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。
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