2013 Fiscal Year Final Research Report
Regulation of autophagy and its impact in the development and progression of hepatocellular cancer.
| Project/Area Number |
23390197
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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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| Research Field |
Gastroenterology
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| Research Institution | Osaka University |
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Principal Investigator |
TAKEHARA Tetsuo 大阪大学, 医学(系)研究科(研究院), 教授 (70335355)
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| Co-Investigator(Kenkyū-buntansha) |
TATSUMI Tomohide 大阪大学, 大学院・医学系研究科, 助教 (20397699)
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| 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
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| Project Period (FY) |
2011-04-01 – 2014-03-31
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| Keywords | オートファジー / 肝細胞癌 / アポトーシス |
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| 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.
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[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 liver2013
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
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Journal Title
J. Biol. Chem
Volume: 288
Pages: 30009-30018
Peer Reviewed
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[Journal Article] Bak deficiency inhibits liver carcinogenesis : a causal link between apoptosis and carcinogenesis2012
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
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Journal Title
J Hepatol
Volume: 57
Pages: 92-100
Peer Reviewed
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[Journal Article] Inhibition of autophagy potentiates the anti-tumor effect of the multi-kinase inhibitor sorafenib in hepatocellular carcinoma2012
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
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Journal Title
Int J Cancer
Volume: 131
Pages: 548-557
Peer Reviewed
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[Presentation] The crosstalk between apoptosis and autophagy in the pathogenesis of non-alcoholic fatty liver disease2013
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
Year and Date
20131102-05
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[Presentation] Oxidative stress induced by continuous hepatocyte apoptosis drives liver carcinogenesis independently of regeneration and DNA methylation status2013
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
Year and Date
20131102-05
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[Presentation] Oxidative stresses play a major role in cancer development in apoptosis-prone liver2012
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
Year and Date
20121109-13
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[Presentation] Bid and Bim are essential regulators involving the intrinsic pathway of apoptosis in hepatocytes in the absence of anti-apoptotic Bcl-2 family proteins2012
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
Year and Date
20121109-13
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[Presentation] Differential roles of palmitic acid and oleic acid in regulation of apoptosis and autophagy in non-alcoholic fatty liver disease2012
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
Year and Date
20121109-13
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