Discovery of cancer genes driving NASH-HCC for personalized therapy
| Project/Area Number |
20H03661
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 53010:Gastroenterology-related
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| Research Institution | Osaka University |
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Principal Investigator |
Kodama Takahiro 大阪大学, 大学院医学系研究科, 助教 (10623275)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
Fiscal Year 2022: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2021: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2020: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
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| Keywords | 肝癌 / 肝細胞癌 / NASH / がん抑制遺伝子 / CRISPR / トランスポゾン / 遺伝子スクリーニング / 肝内胆管癌 / Traf3 / HCC / スクリーニング / ドライバー遺伝子 / プール型ライブラリー |
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| Outline of Research at the Start |
本研究は、非アルコール性脂肪肝炎（NASH）からの肝癌発症・進展の分子メカニズムの解明を目指して、ドライバー遺伝子のカタログを作成することを目的とする。申請者はマウス生体内での癌遺伝子探索技術を用いて、これまでにNASH由来肝癌ドライバー遺伝子候補を多数同定した。本研究ではNASH由来肝癌臨床試料のデータ解析と動物モデルで得られた結果を統合し、独自に開発した新規技術を用いて、ハイスループットな癌ドライバー遺伝子候補の検証並びに機能解析を行う。最終的にはカタログ化されたドライバー遺伝子群を対象としたNASH由来肝癌診断パネルを作成し、個別化医療の実現を目指す。
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| Outline of Final Research Achievements |
We have established a new screening system that can identify hepatocellular carcinoma (HCC) cancer genes in a high-throughput manner by introducing CRISPR/Cas libraries into mouse liver. We aimed to validate a large number of candidate HCC cancer genes obtained from previously-performed transposon insertional mutation screens and found that Sav1, Gsk3b, Setd2, and Lonp2 function as new tumor suppressor genes for NASH-based HCC. In addition, we found that the Traf3 gene regulates the trans-differentiation from hepatocytes to cholangiocytes, and the dysregulation of the Traf3/NIK pathway
promotes intrahepatic cholangiocarcinoma development from hepatocytes via trans-differentiation.
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| Academic Significance and Societal Importance of the Research Achievements |
樹立した新たなマウスシステムは、生体内において肝癌の発症に寄与する分子を効率よく同定できる新しい技術であり、今後肝癌における発症メカニズムの解明や新たな治療標的の同定に応用できる研究成果である。また、本研究で同定された新たな肝癌のがん抑制遺伝子やその下流経路を標的とした肝癌治療薬や予防法開発に繋がる成果と考えられる。肝癌は全世界での死亡者数4位(約78万人)の難治性がんであり、日本国内に3万5千人の患者が存在し、年間死亡者数は2万9千人に上る非常に予後不良な癌である。本研究は治療法開発などを通じた肝癌の予後改善に繋げるための、基礎的に重要な成果であり、社会的意義は大きい。
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Report
(4 results)
Research Products
(49 results)
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[Journal Article] Hepatitis C virus modulates signal peptide peptidase to alter host protein processing.2021
Author(s)
11.Hirano J, Yoshio S, Sakai Y, Songling L, Suzuki T, Itoh Y, Zhang H, Chen DV, Haga S, Oomori H, Kodama T, Maeda Y, Ono Y, Takahashi Y, Standley DM, Yamamoto M, Moriishi K, Moriya K, Kanto T, Takehara T, Koike K, Matsuura Y, Okamoto T.
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Journal Title
Proc Natl Acad Sci U S A.
Volume: 118(22)
Issue: 22
Pages: 2026184118-2026184118
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Transcriptomics Identify Thrombospondin-2 as a Biomarker for Nonalcoholic Steatohepatitis and Advanced Liver Fibrosis2021
Author(s)
Kozumi K, Kodama T, Murai H, Sakane S, Govaere O, Cockell S, Motooka D, Kakita N, Yamada Y, Kondo Y, Tahata Y, Yamada R, Hikita H, Sakamori R, Kamada Y, Daly KA, Anstee MQ, Tatsumi T, Morii E, Takehara T
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Journal Title
Hepatology
Volume: 74(5)
Issue: 5
Pages: 2452-2466
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Hepatic Stellate Cells in Hepatocellular Carcinoma Promote Tumor Growth Via Growth Differentiation Factor 15 Production2021
Author(s)
Myojin Y, Hikita H, Sugiyama M, Sasaki Y, Fukumoto K, Sakane S, Makino Y, Takemura N, Yamada R, Shigekawa M, Kodama T, Sakamori R, Kobayashi S, Tatsumi T, Suemizu H, Eguchi H, Kokudo N, Mizokami M, Takehara T.
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Journal Title
Gastroenterology .
Volume: 160
Issue: 5
Pages: 1741-1754
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Gab1 in livers with persistent hepatocyte apoptosis has an antiapoptotic effect and reduces chronic liver injury, fibrosis and tumorigenesis2021
Author(s)
Mizutani N, Hikita H, Saito Y, Myojin Y, Sato K, Urabe M, Kurahashi T, Shiode Y, Sakane S, Murai K, Nozaki Y, Kodama T, Sakamori R, Yoshida Y, Tatsumi T, Takehara T.
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Journal Title
Am J Physiol Gastrointest Liver Physiol.
Volume: in press
Issue: 6
Pages: G958-G968
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Persistent hepatocyte apoptosis promotes tumorigenesis from diethylnitrosamine-transformed hepatocytes through increased oxidative stress, independent of compensatory liver regeneration2021
Author(s)
Nozaki Y, Hikita H, Tanaka S, Fukumoto K, Urabe M, Sato K, Myojin Y, Doi A, Murai K, Sakane S, Saito Y, Kodama T, Sakamori R, Tatsumi T, Takehara T.
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Journal Title
Sci Rep
Volume: 11
Issue: 1
Pages: 3363-3363
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Sequential administration of XPO1 and ATR inhibitors enhances therapeutic response in TP53-mutated colorectal cancer2021
Author(s)
Inoue A, Robinson FS, Minelli R, Tomihara H, Rizi BS, Rose JL, Kodama T, Srinivasan S, , Stephan C, Giuliani V, Deem AK, Shingu T, Deribe YL, Menter DG, Heffernan TP, Viale A, Bristow CA, Kopetz S, Draetta GF, Genovese G, Carugo A
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Journal Title
Gastroenterology
Volume: in press
Issue: 1
Pages: 196-210
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Presentation] Hepatic stellate cell autophagy promotes HCC progression via GDF152020
Author(s)
Yuta Myojin, Hayato Hikita, Masaya Sugiyama, Takahiro Kodama, Yuki Makino, Ryoko Yamada, Tasuku Nakabori, Ryotaro Sakamori, Tomohide Tatsumi, Masashi Mizokami, Tetsuo Takehara
Organizer
The Digital International Liver Congress of the European Association for the Study of the Liver (EASL)
Related Report
Int'l Joint Research
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