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Discovery of HCC progression-related cancer genes through in vivo forward genetic screen

Research Project

Project/Area Number 17K09422
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Gastroenterology
Research InstitutionOsaka University

Principal Investigator

Takahiro Kodama  大阪大学, 医学系研究科, 助教 (10623275)

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)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
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)
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
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.

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。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (25 results)

All 2020 2019 2018 2017 Other

All Int'l Joint Research (1 results) Journal Article (6 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 6 results) Presentation (18 results) (of which Int'l Joint Research: 4 results,  Invited: 2 results)

  • [Int'l Joint Research] M.D. Anderson Cancer Center(米国)

    • Related Report
      2017 Research-status Report
  • [Journal Article] Forkhead Box M1 Transcription Factor Drives Liver Inflammation Linking to Hepatocarcinogenesis in Mice2020

    • Author(s)
      Kurahashi Tomohide、Yoshida Yuichi、Ogura Satoshi、Egawa Mayumi、Furuta Kunimaro、Hikita Hayato、Kodama Takahiro、Sakamori Ryotaro、Kiso Shinichi、Kamada Yoshihiro、Wang I-Ching、Eguchi Hidetoshi、Morii Eiichi、Doki Yuichiro、Mori Masaki、Kalinichenko Vladimir V.、Tatsumi Tomohide、Takehara Tetsuo
    • Journal Title

      Cellular and Molecular Gastroenterology and Hepatology

      Volume: 9 Issue: 3 Pages: 425-446

    • DOI

      10.1016/j.jcmgh.2019.10.008

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] MRTFB suppresses colorectal cancer development through regulating SPDL1 and MCAM2019

    • Author(s)
      Kodama Takahiro、Marian Teresa A.、Lee Hubert、Kodama Michiko、Li Jian、Parmacek Michael S.、Jenkins Nancy A.、Copeland Neal G.、Wei Zhubo
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 116 Issue: 47 Pages: 23625-23635

    • DOI

      10.1073/pnas.1910413116

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] CRISPR Loss-of-Function Screen Identifies the Hippo Signaling Pathway as the Mediator of Regorafenib Efficacy in Hepatocellular Carcinoma2019

    • Author(s)
      Suemura Shigeki、Kodama Takahiro、Myojin Yuta、Yamada Ryoko、Shigekawa Minoru、Hikita Hayato、Sakamori Ryotaro、Tatsumi Tomohide、Takehara Tetsuo
    • Journal Title

      Cancers

      Volume: 11 Issue: 9 Pages: 1362-1362

    • DOI

      10.3390/cancers11091362

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Molecular profiling of nonalcoholic fatty liver disease-associated hepatocellular carcinoma using SB transposon mutagenesis2018

    • Author(s)
      Kodama Takahiro、Yi Jing、Newberg Justin Y.、Tien Jean C.、Wu Hao、Finegold Milton J.、Kodama Michiko、Wei Zhubo、Tamura Takeshi、Takehara Tetsuo、Johnson Randy L.、Jenkins Nancy A.、Copeland Neal G.
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 115 Issue: 44

    • DOI

      10.1073/pnas.1808968115

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] CTGF Mediates Tumor?Stroma Interactions between Hepatoma Cells and Hepatic Stellate Cells to Accelerate HCC Progression2018

    • Author(s)
      Makino Yuki、Hikita Hayato、Kodama Takahiro、Shigekawa Minoru、Yamada Ryoko、Sakamori Ryotaro、Eguchi Hidetoshi、Morii Eiichi、Yokoi Hideki、Mukoyama Masashi、Hiroshi Suemizu、Tatsumi Tomohide、Takehara Tetsuo
    • Journal Title

      Cancer Research

      Volume: 78 Issue: 17 Pages: 4902-4914

    • DOI

      10.1158/0008-5472.can-17-3844

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] DNase II activated by the mitochondrial apoptotic pathway regulates RIP1-dependent non-apoptotic hepatocyte death via the TLR9/IFN-β signaling pathway2018

    • Author(s)
      Saito Yoshinobu、Hikita Hayato、Nozaki Yasutoshi、Kai Yugo、Makino Yuki、Nakabori Tasuku、Tanaka Satoshi、Yamada Ryoko、Shigekawa Minoru、Kodama Takahiro、Sakamori Ryotaro、Tatsumi Tomohide、Takehara Tetsuo
    • Journal Title

      Cell Death & Differentiation

      Volume: 26 Issue: 3 Pages: 470-486

    • DOI

      10.1038/s41418-018-0131-6

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] プール型CRISPRライブラリースクリーニングによる肝がんレゴラフェニブ効果予測マーカーの探索2020

    • Author(s)
      小玉尚宏、末村茂樹、疋田隼人、阪森亮太郎、巽智秀、竹原徹郎
    • Organizer
      第21回日本肝がん分子標的治療研究会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 生体内forward genetic screenによる肝がんドライバー遺伝子の網羅的探索2019

    • Author(s)
      小玉 尚宏、巽 智秀、竹原 徹郎
    • Organizer
      第105回日本消化器病学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 肝臓におけるHippo/PI3K経路の制御異常はNASH進展と肝癌発症を促進する2019

    • Author(s)
      小玉 尚宏、疋田 隼人、竹原 徹郎
    • Organizer
      第55回日本肝臓学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] In vivo oncogene library screen of predictive biomarkers for multi-kinase inhibitors in hepatocellular carcinoma2019

    • Author(s)
      小玉尚宏、明神悠太、山田涼子、疋田隼人、阪森亮太郎、巽智秀、竹原徹郎
    • Organizer
      第55回日本肝臓学会総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 肝細胞癌においてHippo経路はレゴラフェニブの治療効果を修飾する2019

    • Author(s)
      小玉尚宏、末村茂樹、疋田隼人、阪森亮太郎、巽智秀、竹原徹郎
    • Organizer
      第55回日本肝癌研究会
    • Related Report
      2019 Annual Research Report
  • [Presentation] High-throughput discovery of liver cancer genes by forward genetic screens in mice2019

    • Author(s)
      Takahiro Kodama, Tetsuo Takehara
    • Organizer
      APPLE2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] CRISPR loss-of-function screen identifies the Hippo pathway as the potential efficacy biomarker of regorafenib in HCC2019

    • Author(s)
      Takahiro Kodama, Shigeki Suemura, Yuta Myojin, Hayato Hikita, Ryotaro Sakamori, Tomohide Tatsumi, Tetsuo Takehara
    • Organizer
      第78回日本癌学会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] CRISPR LOSS-OF-FUNCTION SCREEN IDENTIFIES THE HIPPO SIGNALLING PATHWAY AS THE MEDIATOR OF REGORAFENIB EFFICACY IN HEPATOCELLULAR CARCINOMA2019

    • Author(s)
      Takahiro Kodama, Shigeki Suemura, Yuta Myojin, Ryoko Yamada, Hayato Hikita, Ryotaro Sakamori, Tomohide Tatsumi, Tetsuo Takehara
    • Organizer
      AASLD The Liver Meeting 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] In vivo rapid genetic screen of efficacy biomarkers for multi-kinase inhibitors in Hepatocellular carcinoma2019

    • Author(s)
      Takahiro Kodama , Yuta Myojin , Hayato Hikita , Ryotaro Sakamori , Tomohide Tatsumi , Tetsuo Takehara
    • Organizer
      JDDW 2019
    • Related Report
      2019 Annual Research Report
  • [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
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Whole-genome Sleeping Beauty mutagenesis screens identify the Hippo pathway as the driver of NAFLD-related hepatocellular carcinoma2018

    • Author(s)
      Takahiro Kodama, Jing Yi, Justin Y. Newberg, Hao Wu, Milton J. Finegold, Takeshi Tamura, Tetsuo Takehara, Randy L. Johnson, Nancy A. Jenkins, Neal G. Copeland
    • Organizer
      The Liver Meeting 2018 in AASLD
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Forward genetic screens of genes determining the efficacy of molecular target therapy in hepatocellular carcinoma2018

    • Author(s)
      小玉 尚宏, 明神 悠太、疋田 隼人、阪森 亮太郎, 竹原 徹郎
    • Organizer
      第77回日本癌学会大会
    • Related Report
      2018 Research-status Report
  • [Presentation] プール型全ゲノムCRISPR/Casライブラリーを用いた肝癌新規癌抑制遺伝子とソラフェニブ感受性因子探索2018

    • Author(s)
      小玉 尚宏、疋田 隼人, 阪森 亮太郎, 巽 智秀, 竹原 徹郎
    • Organizer
      第54回日本肝臓学会大会
    • Related Report
      2018 Research-status Report
  • [Presentation] 肝がんにおける新規癌抑制遺伝子RNF125の同定と機能解析2018

    • Author(s)
      小玉 尚宏, 末村 茂樹, 村井 大毅, 疋田 隼人, 阪森 亮太郎, 巽 智秀, 竹原 徹郎
    • Organizer
      第54回日本肝臓学会大会
    • Related Report
      2018 Research-status Report
  • [Presentation] NASH肝発がんにおけるHippo経路の意義と治療標的としての有用性2018

    • Author(s)
      小玉 尚宏, 阪森 亮太郎, 竹原 徹郎
    • Organizer
      第54回日本肝臓学会大会
    • Related Report
      2018 Research-status Report
  • [Presentation] トランスポゾンスクリーニングを用いたNASH由来肝癌ドライバー遺伝子の網羅的探索2018

    • Author(s)
      小玉 尚宏, 巽 智秀, 竹原 徹郎
    • Organizer
      第104回日本消化器病学会総会
    • Related Report
      2018 Research-status Report
  • [Presentation] Hippo経路の破綻は脂肪性肝疾患からの肝癌発症のドライバーである2017

    • Author(s)
      小玉尚宏、巽智秀、竹原徹郎
    • Organizer
      JDDW2017
    • Related Report
      2017 Research-status Report
  • [Presentation] Two-step in vivo forward genetic screens in mice discover and validate novel tumor suppressor genes in HCC2017

    • Author(s)
      Takahiro Kodama, Tetsuo Takehara
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2022-02-21  

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