Functional analysis of novel cancer-related gene of HCC identified by RNAi screening method
| Project/Area Number |
16K09357
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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 |
Takai Atsushi 京都大学, 医学研究科, 特定助教 (80760587)
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 肝癌 / 癌幹細胞 / EpCAM / PMPCB / 肝細胞癌 / RNAiスクリーニング / 肝癌抑制 |
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| Outline of Final Research Achievements |
We characterized PMPCB gene, which plays a role in mitochondrial protein processing, as a bona fide target for Epcam positive HCC. PMPCB blocking suppressed EpCAM expression and induced apoptosis specifically in EpCAM positive liver cancer cells in vitro and in vivo. PMPCB inhibition decreased the activity of Wnt/beta-catenin signaling via mitochondria-related reactive oxygen species production and FOXO activities, resulting in apoptosis and tumor suprression. These results indicate that a synthetic lethality screen is a viable strategy to identify actionable drivers of HCC and identify PMPCB as a therapeutically vulnerable gene in EpCAM positive HCC supopulations.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究では、肝癌の幹/前駆細胞を標的とした治療の開発に当たり、肝癌幹/前駆細胞のマーカーであるEpCAMと、global RNAiスクリーニングでEpCAMとsynthetic lethalな関係性を持つ候補分子としてミトコンドリアプロセシングタンパクであるPMPCBに着目し、機能解析を行った。その結果、PMPCBの機能を阻害することで、beta-catenin pathwayの活性を低下させ、EpCAM陽性肝癌細胞のみを選択的にアポトーシスに誘導できることが分かった。本研究成果は、癌幹/前駆細胞を標的とした新しい治療法の開発につながり、今後の肝癌診療の発展に大きく寄与することが期待される。
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Report
(5 results)
Research Products
(16 results)
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[Journal Article] Genome-Wide RNAi Screen Identifies PMPCB as a Therapeutic Vulnerability in EpCAM+ Hepatocellular Carcinoma2019
Author(s)
Atsushi Takai, Hien Dang, Naoki Oishi, Subreen Khatib, Sean P. Martin, Dana A. Dominguez, Ji Luo, Rachel Bagni, Xiaolin Wu, katie Powell, Qing-Hai Ye, Hu-Liang Jia, Lun-Xiu Qin, Jinqiu Chen, Gray A. Mitchell, Xiaoling Luo, Snorri S. Thorgeirsson, Xin Wei Wang
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Journal Title
Cancer Research
Volume: 79
Issue: 9
Pages: 2379-2391
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Evolution of multi-drug resistant HCV clones from pre-existing resistant-associated variants during direct-acting antiviral therapy determined by third-generation sequencing.2017
Author(s)
Takeda H, Ueda Y, Inuzuka T, Yamashita Y, Osaki Y, Nasu A, Umeda M, Takemura R, Seno H, Sekine A, Marusawa H.
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Journal Title
Scientific Reports
Volume: 7
Issue: 1
Pages: 45605-45605
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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