Discovery of HCC progression-related cancer genes through in vivo forward genetic screen
| Project/Area Number |
17K09422
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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 | Osaka University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
巽 智秀 大阪大学, 医学系研究科, 講師 (20397699)
疋田 隼人 大阪大学, 医学系研究科, 助教 (20623044)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | 肝細胞癌 / Hippo経路 / 遺伝子スクリーニング / ノックアウトマウス / CRISPR / NASH / トランスポゾン / Sav1 / Pten / 脱分化 / 肝細胞がん / EMT / CRISPR/Cas / スクリーニング |
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| Outline of Final Research Achievements |
We generated pooled CRISPR library targeting driver gene candidates identified by previous screening. We introduced the library into Pten-deficient and Kras-activated mice and accelerated their tumorigenesis. We sequenced developed tumor and found Indel mutation in Sav1 gene locus. Then, we generated sav1 knockout mice and crossed with Pten knockout mice that spontaneously develop steatohepatitis. These mice rapidly developed multiple liver tumors. Expression levels of SAV1 and PTEN were significantly downregulated in tumor tissues of non-viral HCC patients than their non-tumor tissues and patients with lower levels of those showed poorer prognosis. Taken together, we showed the novel tumor suppressive role of Sav1 gene in HCC.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究により発癌機序に不明な点が多い非アルコール性脂肪性肝疾患由来の肝発癌の新規機序が明らかになった。非アルコール性脂肪性肝疾患患者人口は極めて多いが、その中から肝癌を発症する頻度は決して高くないため、効率の良いスクリーニングが重要である。本研究成果により、発癌機序の一端が明らかになることで、高リスク群の囲い込みに繋がる可能性がある。また、進行肝がんの治療選択肢は少なく、今回同定した新規遺伝子を標的とした治療法の開発に繋がる可能性があると考えられる。以上より、本研究成果は学術的に新規のがん抑制遺伝子を同定・検証したのみならず、社会的意義が極めて大きい結果であると考えられる。
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Report
(4 results)
Research Products
(25 results)
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[Presentation] Whole-genome Sleeping Beauty mutagenesis screens identify the Hippo pathway as the driver of NAFLD-related hepatocellular carcinoma2019
Author(s)
T Kodama, J Yi, J.Y. Newberg, J.C. Tien, H Wu, M.J. Finegold, M Kodama, T Tamura, R.L. Johnson, N.A. Jenkins, T Takehara, N.G. Copeland
Organizer
11th AACR-JCA Joint Conference on Breakthrough in Cancer Reserch
Related Report
Int'l Joint Research
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