Regulation of autophagy and its impact in the development and progression of hepatocellular cancer.

• Project/Area Number: 23390197
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Osaka University
• Principal Investigator: TAKEHARA Tetsuo 大阪大学, 医学(系)研究科(研究院), 教授 (70335355)
• Co-Investigator(Kenkyū-buntansha): TATSUMI Tomohide 大阪大学, 大学院・医学系研究科, 助教 (20397699)
• Co-Investigator(Renkei-kenkyūsha): HIKITA Hayato 大阪大学, 大学院・医学系研究科, 寄附講座助教 (20623044) ; TANAKA Satoshi 大阪大学, 大学院・医学系研究科, 大学院生
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥18,980,000 (Direct Cost: ¥14,600,000、Indirect Cost: ¥4,380,000); Fiscal Year 2013: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2012: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2011: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• Keywords: オートファジー / 肝細胞癌 / アポトーシス / 非アルコール性脂肪肝炎 / 脂肪肝炎 / Atg7 / Mcl-1 / ノックアウトマウス / ソラフェニブ / Atg-7

Research Abstract

The aim was to clarify the relationship between apoptosis and autophagy in the pathogenesis of non-alcoholic steatohepatitis, and also in the treatment of hepatocellular carcinoma (HCC). Excess free fatty acids suppressed autophagic flux in hepatocytes and induced apoptosis by increasing endoplasmic reticulum stress. Hepatocyte-specific Mcl-1 knockout mice revealed that chronically increased hepatocyte apoptosis leads to liver fibrosis and cancer, suggesting that, in the pathogenesis of steatohepatitis, continuous hepatocyte apoptosis induced by autophagy impairment contributes to hepatic fibrogenesis and carcinogenesis. Finally, sorafenib, a multikinase inhibitor for the treatment of HCC, enhanced autophagic activity, which then inhibited apoptosis in hepatoma cells. In conclusion, autophagy may be a double-edged sword in the liver cancer development and progression; the promotion promotes the survival of the cancer cells while the restraint promotes the outbreak of cancer.

Research Products

• [Journal Article] The Bcl-2 homology 3 (BH3)-only proteins Bim and Bid are functionally active and restrained by anti-apoptotic B-cell CLL/lymphoma 2 (Bcl-2) family proteins in healthy liver (2013)
  • Author(s): Kodama T, Hikita H, Kawaguchi T, Saito Y, Tanaka S, Shigekawa M, Shimizu S, Li W, Miyagi T, Kanto T, Hiramatsu N, Tatsumi T, Takehara T
  • Journal Title: J. Biol. Chem Volume: 288 Pages: 30009-30018
  • Peer Reviewed
• [Journal Article] The Bcl-2 homology 3 (BH3)-only proteins Bim and Bid are functionally active and restrained by anti-apoptotic B-cell CLL/lymphoma 2 (Bcl-2) family proteins in healthy liver. (2013)
  • Author(s): [1] Kodama T, Hikita H, Kawaguchi T, Saito Y, Tanaka S, Shigekawa M, Shimizu S, Li W, Miyagi T, Kanto T, Hiramatsu N, Tatsumi T, Takehara T.
  • Journal Title: J. Biol. Chem. Volume: 288 Issue: 42 Pages: 30009-30018
  • DOI: 10.1074/jbc.m112.443093
  • Peer Reviewed
• [Journal Article] Bak deficiency inhibits liver carcinogenesis : a causal link between apoptosis and carcinogenesis (2012)
  • Author(s): Hikita H, Kodama T, Shimizu S, Li W, Shigekawa M, Tanaka S, Hosui A, Miyagi T, Tatsumi T, Kanto T, Hiramatsu N, Morii E, Hayashi N, Takehara T
  • Journal Title: J Hepatol Volume: 57 Pages: 92-100
  • Peer Reviewed
• [Journal Article] Inhibition of autophagy potentiates the anti-tumor effect of the multi-kinase inhibitor sorafenib in hepatocellular carcinoma (2012)
  • Author(s): Shimizu S, Takehara T, Hikita H, Kodama T, Tsunematsu H, Miyagi T, Hosui A, Ishida H, Tatsumi T, Kanto T, Hiramatsu N, Fujita N, Yoshimori T, Hayashi N
  • Journal Title: Int J Cancer Volume: 131 Pages: 548-557
  • Peer Reviewed
• [Journal Article] Bak deficiency inhibits liver carcinogenesis : A causal link between apoptosis and carcinogenesis (2012)
  • Author(s): Hikita H, Takehara T, et al
  • Journal Title: Journal of Hepatology Volume: (印刷中) Issue: 1 Pages: 92-100
  • DOI: 10.1016/j.jhep.2012.01.027
  • Peer Reviewed
• [Journal Article] Inhibition of autophagy potentiates the antitumor effect of the multikinase inhibitor sorafenib in hepatocellular carcinoma (2011)
  • Author(s): Shimizu S, Takehara T, Hikita H, Kodama T, Tsunematsu H, Miyagi T, Hosui A, Ishida H, Tatsumi T, Kanto T, Hiramatsu N, Fujita N, Yoshimori T, Hayashi N
  • Journal Title: Int.J.Cancer Volume: 131 Issue: 3 Pages: 548-57
  • DOI: 10.1002/ijc.26374
  • Peer Reviewed
• [Journal Article] Increases ill p53 expression induce CTGF synthesis by mouse and human hepatocytes and result in liver fibrosis in mice (2011)
  • Author(s): Kodama, T., et al
  • Journal Title: J.Clin.Invest. Volume: 121 Issue: 8 Pages: 3343-3356
  • DOI: 10.1172/jci44957
  • Peer Reviewed
• [Presentation] The crosstalk between apoptosis and autophagy in the pathogenesis of non-alcoholic fatty liver disease (2013)
  • Author(s): Satoshi Tanaka, Hayato Hikita, Tasuku Nakabori, Yoshinobu Saito, Satoshi Shimizu, Wei Li, Ryotaro Sakamori, Takuya Miyagi, Naoki Hiramatsu, Tomohide Tatsumi, Tetsuo Takehara
  • Organizer: The 64th Annual Meeting of the American Association for the study of Liver Disease. The crosstalk between apoptosis and autophagy in the pathogenesis of non-alcoholic fatty liver disease
  • Place of Presentation: Washington, USA
• [Presentation] Oxidative stress induced by continuous hepatocyte apoptosis drives liver carcinogenesis independently of regeneration and DNA methylation status (2013)
  • Author(s): Hayato Hikita, Tomohide Tatsumi, Yoshinobu Saito, Satoshi Tanaka, Satoshi Shimizu, Wei Li, Ryotaro Sakamori, Takuya Miyagi, Naoki Hiramatsu, Tetsuo Takehara
  • Organizer: The 64th Annual Meeting of the American Association for the study of Liver Disease
  • Place of Presentation: Washington, USA
• [Presentation] NAFLD/NASH 病態形成における, 飽和脂肪酸・不飽和脂肪酸によるオートファジーとアポトーシスの制御に関して (2013)
  • Author(s): 田中聡司, 疋田隼人, 齋藤義修, 清水聡, 阪森亮太郎, 宮城琢也, 巽智秀, 竹原徹郎
  • Organizer: 第49回肝臓学会総会
  • Place of Presentation: 東京
• [Presentation] 肝細胞アポトーシスが発生する酸化ストレスの肝発癌に与える影響 (2013)
  • Author(s): 疋田隼人, 巽智秀, 宮城琢也, 阪森亮太郎, 清水聡, 斉藤義修, 田中聡司, 竹原徹郎
  • Organizer: 第49回肝臓学会総会
  • Place of Presentation: 東京
• [Presentation] NASH 肝障害・肝発癌の病態形成における, オートファジー抑制を介した持続的アポトーシスの寄与 (2013)
  • Author(s): 田中聡司, 疋田隼人, 齋藤義修, 清水聡, 阪森亮太郎, 宮城琢也, 巽智秀, 竹原徹郎
  • Organizer: 第17回日本肝臓学会大会
  • Place of Presentation: 東京
• [Presentation] 慢性肝障害からの肝発癌におけるバイオマーカーの検討 (2013)
  • Author(s): 疋田隼人, 巽智秀, 中堀輔, 斎藤義修, 田中聡司, 清水聡, 阪森亮太郎, 宮城拓也, 竹原徹郎
  • Organizer: 第17回日本肝臓学会大会
  • Place of Presentation: 東京
• [Presentation] The crosstalk between apoptosis and autophagy in the pathogenesis of non-alcoholic fatty liver disease. (2013)
  • Author(s): Satoshi Tanaka, Hayato Hikita, Tasuku Nakabori, Yoshinobu Saito, Satoshi Shimizu, Wei Li, Ryotaro Sakamori, Takuya Miyagi, Naoki Hiramatsu, Tomohide Tatsumi, Tetsuo Takehara.
  • Organizer: The 64th Annual Meeting of the American Association for the study of Liver Disease.
  • Place of Presentation: Washington D.C., USA
• [Presentation] .Oxidative stress induced by continuous hepatocyte apoptosis drives liver carcinogenesis independently of regeneration and DNA methylation status. (2013)
  • Author(s): Hayato Hikita, Tomohide Tatsumi, Yoshinobu Saito, Satoshi Tanaka, Satoshi Shimizu, Wei Li, Ryotaro Sakamori, Takuya Miyagi, Naoki Hiramatsu, Tetsuo Takehara.
  • Organizer: The 64th Annual Meeting of the American Association for the study of Liver Disease.
  • Place of Presentation: Washington D.C., USA
• [Presentation] NAFLD/NASH病態形成における、飽和脂肪酸・不飽和脂肪酸によるオートファジーとアポトーシスの制御に関して. (2013)
  • Author(s): 田中聡司、疋田隼人、齋藤義修、清水聡、阪森亮太郎、宮城琢也、巽智秀、竹原徹郎
  • Organizer: 第４９回日本肝臓学会総会
  • Place of Presentation: 東京
• [Presentation] 肝細胞アポトーシスが発生する酸化ストレスの肝発癌に与える影響 (2013)
  • Author(s): 疋田隼人、巽智秀、宮城琢也、阪森亮太郎、清水聡、斉藤義修、田中聡司、竹原徹郎
  • Organizer: 第４９回肝臓学会総会
  • Place of Presentation: 東京
• [Presentation] NASH肝障害・肝発癌の病態形成における、オートファジー抑制を介した持続的アポトーシスの寄与 (2013)
  • Author(s): 田中聡司、疋田隼人、齋藤義修、清水聡、阪森亮太郎、宮城琢也、巽智秀、竹原徹郎.
  • Organizer: 第１７回日本肝臓学会大会
  • Place of Presentation: 東京
• [Presentation] 慢性肝障害からの肝発癌におけるバイオマーカーの検討 (2013)
  • Author(s): 疋田隼人、巽智秀、中堀輔、斎藤義修、田中聡司、清水聡、阪森亮太郎、宮城拓也、竹原徹郎
  • Organizer: 第１７回日本肝臓学会大会
  • Place of Presentation: 東京
• [Presentation] Oxidative stresses play a major role in cancer development in apoptosis-prone liver (2012)
  • Author(s): Hayato Hikita, Takahiro Kodama, Satoshi Tanaka, Yoshinobu Saito, Satoshi Shimizu, Minoru Shigekawa, Wei Li, Takuya Miyagi, Tatsuya Kanto, Naoki Hiramatsu, Tomohide Tatsumi, Tetsuo Takehara
  • Organizer: The 63rd Annual Meeting of the American Association for the study of Liver Disease
  • Place of Presentation: Boston, USA
• [Presentation] Bid and Bim are essential regulators involving the intrinsic pathway of apoptosis in hepatocytes in the absence of anti-apoptotic Bcl-2 family proteins (2012)
  • Author(s): Takahiro Kodama, Hayato Hikita, Tsukasa Kawaguchi, Hinako Tsunematsu, Kumiko Nishio, Takatoshi Nawa, Minoru Shigekawa, Satoshi Shimizu, Wei Li, Takuya Miyagi, Atsushi Hosui, Tomohide Tatsumi, Tatsuya Kanto, Naoki Hiramatsu, Tetsuo Takehara
  • Organizer: The 63rd Annual Meeting of the American Association for the study of Liver Disease
  • Place of Presentation: Boston, USA
• [Presentation] Differential roles of palmitic acid and oleic acid in regulation of apoptosis and autophagy in non-alcoholic fatty liver disease (2012)
  • Author(s): Satoshi Tanaka, Hayato Hikita1, Satoshi Aono, Tsukasa Kawaguchi, Kaori Mukai, Satoshi Shimizu, Takahiro Kodama, Wei Li, Takuya Miyagi, Tatsuya Kanto, Naoki Hiramatsu, Tomohide Tatsumi, Tetsuo Takehara
  • Organizer: The 63rd Annual Meeting of the American Association for the study of Liver Disease
  • Place of Presentation: Boston, USA
• [Presentation] The BH3-only proteins, Bim and Bid, constitutively participate in the healthy Bcl-2 rheostat regulating hepatocyte life and death via the mitochondrial pathway of apoptosis. (2012)
  • Author(s): Kodama T, Takehara T, et al.
  • Organizer: The American Association for the Study of Liver Diseases (AASLD), 63rd Annual Meeting
  • Place of Presentation: Boston, USA
• [Presentation] Oxidative stresses play a major role in cancer development in apoptosis-prone liver. (2012)
  • Author(s): Hikita H, Takehara T, et al.
  • Organizer: The American Association for the Study of Liver Diseases (AASLD), 63rd Annual Meeting
  • Place of Presentation: Boston, USA
• [Presentation] Differential roles of palmitic acid and oleic acid in regulation of apoptosis and autophagy in non-alcoholic fatty liver disease. (2012)
  • Author(s): Tanaka S, Takehara T, et al.
  • Organizer: The American Association for the Study of Liver Diseases (AASLD), 63rd Annual Meeting
  • Place of Presentation: Boston, MA
• [Presentation] Multi-kinase inhibitor sorafenib induces autophagy which confers anti-cancer drug resistance to human hepatoma cells (2011)
  • Author(s): Shimizu S, Takehara T, et al
  • Organizer: The American Association for the Study of Liver Diseases (AASLD), 62nd Annual Meeting
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2011-11-08
• [Book] 肝細胞死の研究と進歩, Annual Review 消化器 (2014)
  • Author(s): 疋田隼人, 竹原徹郎, 林紀夫, 日比紀文, 上西紀夫, 下瀬川徹
  • Publisher: 中外医学社
• [Book] Annual Review消化器 2014 (2014)
  • Author(s): 疋田隼人、 竹原徹郎.
  • Publisher: 中外医学社
• [Book] Hepatology Practice 2 NASH・アルコール性肝障害の診療を極める (2013)
  • Author(s): 竹井謙之, 竹原徹郎, 持田智
  • Publisher: 文光堂
• [Book] Hepatology Practice 2 NASH・アルコール性肝障害の診療を極める. (2013)
  • Author(s): 竹井謙之,竹原徹郎, 持田 智.
  • Publisher: 文光堂
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/gh/research_a.html
• [Remarks] 大阪大学大学院医学系研究科内科系臨床医学専攻消化器内科学
  • URL: http://www.med.osaka-u.ac.jp/pub/gh/research_new.html
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/gh/data/relations/study_a.html