Multi-omics analysis for the change of hepatocyte property in the early stages of intrahepatic cholangiocarcinoma

• Project/Area Number: 17K19603
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology and related fields
• Research Institution: Kyushu University
• Principal Investigator: Suzuki Atsushi 九州大学, 生体防御医学研究所, 教授 (30415195)
• Project Period (FY): 2017-06-30 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2018: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2017: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: 肝内胆管がん / 肝細胞 / 分化 / トランスオミクス / 癌 / 細胞・組織 / 遺伝子 / 蛋白質

Outline of Final Research Achievements

In our previous study, we found that intrahepatic cholangiocarcinoma (ICC) can be generated by biliary lineage cells derived from hepatocytes. However, the change of hepatocyte property in the early stages of ICC remains largely unknown. Thus, in this study, we investigated the hepatocyte properties changing in the injured liver and the effect of hepatocyte abnormality in the liver. Our multi-omics analysis revealed the change of epigenetic and metabolic states and gene expression pattern of hepatocytes after the particular injury that can induce the onset of ICC. In addition, we found that enforced Snail expression in hepatocytes is sufficient for induction of steatohepatitis and liver tumorigenesis through disruption of the biliary canaliculus and bile acid homeostasis in the liver. Our findings will be useful for uncovering the pathogenic mechanism of ICC and developing prevenient and therapeutic strategies for this refractory disease.

Academic Significance and Societal Importance of the Research Achievements

本研究によって得られた知見を基盤としてさらに研究を発展させることにより、肝内胆管がんの発症機構をシステムとして理解することが可能になり、肝内胆管がんの早期診断や治療法の開発につながる情報を取得できるようになると考えられる。また、本研究で得られた結果から、肝細胞におけるSnailの過剰発現が胆管上皮細胞への分化転換を阻害すると考えられることから、肝内胆管がんの発症機構を考える上で重要な知見を得ることができた。これは、肝細胞を標的とした薬剤の開発が肝内胆管がんの治療や予防において有効であることを示唆しており、今後の展開が期待される。

Research Products

• [Int'l Joint Research] Universite catholique de Louvain/University of Liege(ベルギー)
• [Int'l Joint Research] Washington University School of Medicine(米国)
• [Int'l Joint Research] Universite catholique de Louvain/University of Liege(ベルギー)
• [Int'l Joint Research] Washington University School of Medicine(米国)
• [Journal Article] Induction of steatohepatitis and liver tumorigenesis by enforced Snail expression in hepatocytes (2020)
  • Author(s): Miura, S. and Suzuki, A.
  • Journal Title: The American Journal of Pathology Volume: in press Issue: 6 Pages: 1271-1283
  • DOI: 10.1016/j.ajpath.2020.02.005
  • Peer Reviewed
• [Journal Article] Zfp281 shapes the transcriptome of trophoblast stem cells and is essential for placental development (2019)
  • Author(s): Ishiuchi, T., Ohishi, H., Sato, T., Kamimura, S., Yorino, M., Abe, S., Suzuki, A., Wakayama, T., Suyama, M., Sasaki, H.
  • Journal Title: Cell Reports Volume: 27 Issue: 6 Pages: 1742-1754
  • DOI: 10.1016/j.celrep.2019.04.028
  • Peer Reviewed / Open Access
• [Journal Article] New high-throughput screen identifies compounds that reduce viability specifically in liver cancer cells that express high levels of SALL4 by inhibiting oxidative phosphorylation (2019)
  • Author(s): Tan, J.L., Li, F., Yeo, J.Z., Yong, K.J., Bassal, M.A., Ng, G.H., Lee, M.Y., Leong, C.Y., Tan, H.K., Wu, C.S., Liu, B.H., Chan, T.H., Tan, Z.H., Chan, Y.S., Wang, S., Lim, Z.H., Toh, T.B., Hooi, L., Low, K.N., Ma, S., Kong, N.R., Stein, A.J., Wu, Y., Thangavelu, M.T., Suzuki, A., et al.
  • Journal Title: Gastroenterology Volume: 157 Issue: 6 Pages: 1615-1629
  • DOI: 10.1053/j.gastro.2019.08.022
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Generation of Nanog reporter mice that distinguish pluripotent stem cells from unipotent primordial germ cells. (2019)
  • Author(s): Terada M, Kawamata M, Kimura R, Sekiya S, Nagamatsu G, Hayashi K, Horisawa K, Suzuki A.
  • Journal Title: Genesis Volume: 57 Issue: 11-12
  • DOI: 10.1002/dvg.23334
  • Peer Reviewed
• [Journal Article] Cell aggregation culture induces functional differentiation of induced hepatocyte-like cells through activation of Hippo signaling (2018)
  • Author(s): Yamamoto, J., Udono, M., Miura, S., Sekiya, S., Suzuki, A.
  • Journal Title: Cell Reports Volume: 25 Issue: 1 Pages: 183-198
  • DOI: 10.1016/j.celrep.2018.09.010
  • Peer Reviewed / Open Access
• [Journal Article] Prolonged inhibition of hepatocellular carcinoma cell proliferation by combinatorial expression of defined transcription factors (2018)
  • Author(s): Takashima Yasuo、Horisawa Kenichi、Udono Miyako、Ohkawa Yasuyuki、Suzuki Atsushi
  • Journal Title: Cancer Science Volume: 109 Issue: 11 Pages: 3543-3553
  • DOI: 10.1111/cas.13798
  • Peer Reviewed / Open Access
• [Journal Article] Brief summary of the current protocols for generating intestinal organoids (2018)
  • Author(s): Miura, S. and Suzuki, A.
  • Journal Title: Development, Growth & Differentiation Volume: 60 Issue: 6 Pages: 387-392
  • DOI: 10.1111/dgd.12559
  • Peer Reviewed
• [Journal Article] Cell fate modification toward the hepatic lineage by extrinsic factors (2017)
  • Author(s): Kawamata Masaki、Suzuki Atsushi
  • Journal Title: The Journal of Biochemistry Volume: 162 Issue: 1 Pages: 11-16
  • DOI: 10.1093/jb/mvx028
  • Peer Reviewed
• [Journal Article] Chd2 regulates chromatin for proper gene expression toward differentiation in mouse embryonic stem cells (2017)
  • Author(s): Semba Yuichiro、Harada Akihito、Maehara Kazumitsu、Oki Shinya、Meno Chikara、Ueda Jun、Yamagata Kazuo、Suzuki Atsushi、Onimaru Mitsuho、Nogami Jumpei、Okada Seiji、Akashi Koichi、Ohkawa Yasuyuki
  • Journal Title: Nucleic Acids Research Volume: 45 Issue: 15 Pages: 8758-8772
  • DOI: 10.1093/nar/gkx475
  • Peer Reviewed / Open Access
• [Journal Article] Generation of Mouse and Human Organoid-Forming Intestinal Progenitor Cells by Direct Lineage Reprogramming (2017)
  • Author(s): Miura Shizuka、Suzuki Atsushi
  • Journal Title: Cell Stem Cell Volume: 21 Issue: 4 Pages: 456-471
  • DOI: 10.1016/j.stem.2017.08.020
  • Peer Reviewed / Open Access
• [Presentation] Trans-omic analysis for metabolic remodeling during liver regeneration (2020)
  • Author(s): Horisawa, K., Miura, S., Izumi, Y., Bamba, T., Suzuki, A.
  • Organizer: The 29th Hot Spring Harbor International Symposium “Cutting Edge of Technical Innovations in Trans-Omics”
  • Int'l Joint Research
• [Presentation] Direct reprogramming to hepatic and intestinal lineages (2019)
  • Author(s): Suzuki, A.
  • Organizer: International Symposium: Principles of pluripotent stem cells underlying plant vitality
  • Int'l Joint Research / Invited
• [Presentation] Generation of induced intestinal stem and progenitor cells by direct lineage reprogramming (2019)
  • Author(s): Suzuki, A.
  • Organizer: The Copenhagen Bioscience Conference on Intestinal Organoids - from stem cells to metabolism and microbiome interactions
  • Int'l Joint Research / Invited
• [Presentation] ダイレクトリプログラミングによるヒト肝前駆細胞の作製 (2019)
  • Author(s): 稲田浩気，鈴木淳史
  • Organizer: PHILOSOPHY
• [Presentation] ダイレクトリプログラミングによる機能性肝細胞の作出と肝再生医療 (2019)
  • Author(s): 鈴木淳史
  • Organizer: 第31回JBICバイオ関連基盤技術研究会「肝疾患（NAFLD/NASH）と肝再生医療」
  • Invited
• [Presentation] 由来の異なる組織由来iHep細胞における遺伝子発現の比較解析 (2019)
  • Author(s): 鵜殿美弥子，堀澤健一，村山僚，鈴木淳史
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] CRISPR-Cas9の活性調節によるアレル選択的ゲノム編集法の開発 (2019)
  • Author(s): 川又理樹，木村亮太，鈴木淳史
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] 転写因子が引き起こすエピジェネティックリモデリングと細胞運命転換 (2019)
  • Author(s): 鈴木淳史
  • Organizer: 第42回日本分子生物学会年会
  • Invited
• [Presentation] 肝臓と腸上皮組織におけるダイレクトリプログラミング研究の進展 (2019)
  • Author(s): 鈴木淳史
  • Organizer: 琉球医学会特別講演会
  • Invited
• [Presentation] ダイレクトリプログラミングによる細胞創生と医療応用 (2019)
  • Author(s): 鈴木淳史
  • Organizer: 九州大学母子総合研究リサーチコアカンファレンス
  • Invited
• [Presentation] Direct reprogramming to hepatic and intestinal lineages (2019)
  • Author(s): Suzuki, A.
  • Organizer: International Symposium on Epigenome 2019
  • Int'l Joint Research / Invited
• [Presentation] ダイレクトリプログラミングによる肝細胞誘導の標準化 (2019)
  • Author(s): 鈴木淳史
  • Organizer: 第18回日本再生医療学会総会
  • Invited
• [Presentation] Direct reprogramming to hepatic and intestinal lineages (2018)
  • Author(s): 鈴木淳史
  • Organizer: 第33回九州免疫血液研究会
  • Invited
• [Presentation] ダイレクトリプログラミングによる腸上皮オルガノイドの作製 (2018)
  • Author(s): 鈴木淳史
  • Organizer: 第18回GIリサーチフォーラム
  • Invited
• [Presentation] 肝細胞におけるsnailの過剰発現は肝細胞癌を誘導する (2018)
  • Author(s): 三浦静、鈴木淳史
  • Organizer: 第25回肝細胞研究会
• [Presentation] 肝細胞へのダイレクトリプログラミングを阻害する転写因子の同定 (2018)
  • Author(s): 従野雅義、堀澤健一、鈴木淳史
  • Organizer: 第25回肝細胞研究会
• [Presentation] 線維芽細胞の不均一性がiHep細胞誘導に与える影響 (2018)
  • Author(s): 後藤那奈子、鵜殿美弥子、鈴木淳史
  • Organizer: 第25回肝細胞研究会
• [Presentation] 転写因子が引き起こすエピジェネティックリモデリングと細胞運命転換 (2018)
  • Author(s): 鈴木淳史
  • Organizer: 日本人類遺伝学会第63回大会
  • Invited
• [Presentation] Identification of transcription factors repressing direct conversion of mouse embryonic fibroblasts into induced hepatocyte-like cells (2018)
  • Author(s): Yorino, M., Horisawa, K., Suzuki, A.
  • Organizer: The 28th Hot Spring Harbor Symposium
  • Int'l Joint Research
• [Presentation] Direct reprogramming to hepatic and intestinal lineages (2018)
  • Author(s): Suzuki, A.
  • Organizer: 2018 The 14th Annual Meeting of TSSCR: From Pluripotency to 3D Organoid and Personalized Medicine
  • Int'l Joint Research / Invited
• [Presentation] Direct reprogramming to hepatic and intestinal lineages (2018)
  • Author(s): 鈴木淳史
  • Organizer: 第41回日本分子生物学会年会
  • Invited
• [Presentation] ダイレクトリプログラミングによるオルガノイド形成能を有するマウスおよびヒト腸前駆細胞の作製 (2018)
  • Author(s): 三浦静、鈴木淳史
  • Organizer: 新学術領域「幹細胞老化と疾患」「細胞競合」総括班主催「若手の会」
• [Presentation] ダイレクトリプログラミングによる腸前駆細胞の作製 (2018)
  • Author(s): 鈴木淳史
  • Organizer: 第7回Hepato-Diabetology Conference
  • Invited
• [Presentation] ダイレクトリプログラミングによるオルガノイド形成能を有するマウスおよびヒト腸前駆細胞の作製 (2018)
  • Author(s): 三浦静、鈴木淳史
  • Organizer: 第17回日本再生医療学会総会
• [Presentation] Direct reprogramming to hepatic and intestinal lineages (2017)
  • Author(s): Suzuki Atsushi
  • Organizer: The 27th Hot Spring Harbor International Symposium “Frontiers in Stem Cell Research and Reprogramming”
  • Int'l Joint Research / Invited
• [Remarks] 研究室ホームページ
  • URL: http://www.bioreg.kyushu-u.ac.jp/labo/orgreg/top.html
• [Patent(Industrial Property Rights)] ゲノム編集された細胞の製造方法 (2018)
  • Inventor(s): 鈴木淳史、川又理樹
  • Industrial Property Rights Holder: 鈴木淳史、川又理樹
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-232946
  • Filing Date: 2018