Functional analysis of novel cancer-related gene of HCC identified by RNAi screening method

• Project/Area Number: 16K09357
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kyoto University
• Principal Investigator: Takai Atsushi 京都大学, 医学研究科, 特定助教 (80760587)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥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)
• 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

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.

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。

Research Products

• [Journal Article] Genome-Wide RNAi Screen Identifies PMPCB as a Therapeutic Vulnerability in EpCAM+ Hepatocellular Carcinoma (2019)
  • 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
  • Journal Title: Cancer Research Volume: 79 Issue: 9 Pages: 2379-2391
  • DOI: 10.1158/0008-5472.can-18-3015
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Utility of ultrasound‐guided liver tumor biopsy for next‐generation sequencing‐based clinical sequencing (2019)
  • Author(s): Eso Yuji、Kou Tadayuki、Nagai Hiroki、Kim Young Hak、Kanai Masashi、Matsumoto Shigemi、Mishima Masako、Arasawa Soichi、Iguchi Eriko、Nakamura Fumiyasu、Takeda Haruhiko、Takai Atsushi、Takahashi Ken、Ueda Yoshihide、Muto Manabu、Seno Hiroshi
  • Journal Title: Hepatology Research Volume: 印刷中 Issue: 5 Pages: 579-589
  • DOI: 10.1111/hepr.13312
  • Peer Reviewed
• [Journal Article] Comprehensive analysis of genetic aberrations linked to tumorigenesis in regenerative nodules of liver cirrhosis (2019)
  • Author(s): Kim Soo Ki、Takeda Haruhiko、Takai Atsushi、Matsumoto Tomonori、Kakiuchi Nobuyuki、Yokoyama Akira、Yoshida Kenichi、Kaido Toshimi、Uemoto Shinji、Minamiguchi Sachiko、Haga Hironori、Shiraishi Yuichi、Miyano Satoru、Seno Hiroshi、Ogawa Seishi、Marusawa Hiroyuki
  • Journal Title: Journal of Gastroenterology Volume: 印刷中 Issue: 7 Pages: 628-640
  • DOI: 10.1007/s00535-019-01555-z
  • Peer Reviewed / Open Access
• [Journal Article] Combination of Mac-2 Binding Protein Glycosylation Isomer and Up-To-Seven Criteria as a Useful Predictor for Child-Pugh Grade Deterioration after Transarterial Chemoembolization for Hepatocellular Carcinoma (2019)
  • Author(s): Eso Yuji、Takai Atsushi、Takahashi Ken、Ueda Yoshihide、Taura Kojiro、Marusawa Hiroyuki、Seno Hiroshi
  • Journal Title: Cancers Volume: 11 Issue: 3 Pages: 405-405
  • DOI: 10.3390/cancers11030405
  • Peer Reviewed / Open Access
• [Journal Article] Association of Mac-2-binding protein glycosylation isomer level with nutritional status in chronic liver disease (2018)
  • Author(s): Eso Yuji、Takai Atsushi、Taura Kojiro、Takahashi Ken、Ueda Yoshihide、Marusawa Hiroyuki、Seno Hiroshi
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: 印刷中 Issue: 9 Pages: 1649-1658
  • DOI: 10.1111/jgh.14130
  • Peer Reviewed
• [Journal Article] Genetic features of multicentric/multifocal intramucosal gastric carcinoma (2018)
  • Author(s): Mizuguchi Aya、Takai Atsushi、Shimizu Takahiro、Matsumoto Tomonori、Kumagai Ken、Miyamoto Shin'ichi、Seno Hiroshi、Marusawa Hiroyuki
  • Journal Title: International Journal of Cancer Volume: 143 Issue: 8 Pages: 1923-1934
  • DOI: 10.1002/ijc.31578
  • Peer Reviewed
• [Journal Article] Ultrasound-guided microfoam sclerotherapy with polidocanol for symptomatic giant hepatic cyst: Initial experience (2018)
  • Author(s): Eso Yuji、Furuta Akihiro、Takai Atsushi、Takahashi Ken、Ueda Yoshihide、Marusawa Hiroyuki、Seno Hiroshi
  • Journal Title: Hepatology Research Volume: 48 Issue: 12 Pages: 1055-1063
  • DOI: 10.1111/hepr.13202
  • Peer Reviewed
• [Journal Article] Oncogenic Activation of the RNA Binding Protein NELFE and MYC Signaling in Hepatocellular Carcinoma (2017)
  • Author(s): Dang Hien、Takai Atsushi、Forgues Marshonna、Pomyen Yotsowat、Mou Haiwei、Xue Wen、Ray Debashish、Ha Kevin C.H.、Morris Quaid D.、Hughes Timothy R.、Wang Xin Wei
  • Journal Title: Cancer Cell Volume: 32 Issue: 1 Pages: 101-114.e8
  • DOI: 10.1016/j.ccell.2017.06.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Proliferating EpCAM-Positive Ductal Cells in the Inflamed Liver Give Rise to Hepatocellular Carcinoma (2017)
  • Author(s): Matsumoto Tomonori、Takai Atsushi、Eso Yuji、Kinoshita Kazuo、Manabe Toshiaki、Seno Hiroshi、Chiba Tsutomu、Marusawa Hiroyuki
  • Journal Title: Cancer Research Volume: 77 Issue: 22 Pages: 6131-6143
  • DOI: 10.1158/0008-5472.can-17-1800
  • Peer Reviewed
• [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.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 45605-45605
  • DOI: 10.1038/srep45605
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic basis of hepatitis virus-associated hepatocellular carcinoma: linkage between infection, inflammation, and tumorigenesis. (2017)
  • Author(s): Takeda H, Takai A, Inuzuka T, Marusawa H.
  • Journal Title: Journal of Gastroenterology Volume: 52 Issue: 1 Pages: 26-38
  • DOI: 10.1007/s00535-016-1273-2
  • Peer Reviewed
• [Presentation] トランスクリプトーム解析を用いた肝硬変再生結節の発癌ポテンシャルの評価 (2018)
  • Author(s): 竹田治彦、高井淳、金秀基、井口恵里子、荒澤荘一、熊谷健、恵荘裕嗣、清水孝洋、高橋健、上田佳秀、丸澤宏之、妹尾浩
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Sulfatase 2-TGFb1-SMADシグナル伝達によるPeriostinの誘導が肝細胞癌において血管新生に寄与する (2018)
  • Author(s): 井口恵里子、高井淳、上田佳秀、妹尾浩
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Identification of novel cancer driver genes in hepatocellular carcinoma cells by RNAi screening method (2017)
  • Author(s): Takai Atsushi, Dang Hien, Oishi Naoki, Wang Xin Wei
  • Organizer: AACR Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] Characterization of hepatocellular carcinoma based on cellular origins (2017)
  • Author(s): Takai Atsushi, Matsumoto Tomonori, Eso Yuji, Kinoshita Kazuo, Chiba Tsutomu, Seno Hiroshi, Marusawa Hiroyuki
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Genetic features of hepatocellular carcinoma arising after eradication of hepatitis C virus (2017)
  • Author(s): Takeda Haruhiko, Takai Atsushi, Kim Soo Ki, Kakiuchi Nobuyuki, Seno Hiroshi, Ogawa Seishi, Marusawa Hiroyuki
  • Organizer: 第76回日本癌学会学術総会