The impact of chemotherapy on innate immune system and cell death signaling in liver cancer.

• Project/Area Number: 24790694
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Osaka University
• Principal Investigator: SHIMIZU Satoshi 大阪大学, 医学部附属病院, 医員 (90623041)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 肝癌 / 細胞死

Research Abstract

In this project, we aimed to clarify the impact of chemotherapy on innate immune system and cell death signaling in liver cancer, which may provide insights to improve the therapeutic outcome. First, we studied the effect of 5-FU in mice with metastatic liver cancer. 5-FU treatment resulted in an upregulation of NKG2D activating molecules. Depletion of NK cells inhibited the antitumor efficacy of 5-FU. Combination therapy of aGalCer and 5-FU showed a synergistic antitumor effect. Regarding the effect on cell death signaling, we examined the expression of RIPK3 in Huh7 cells in vitro. When Huh7 cells were treated with sorafenib, increased expression of RIPK3 was observed by western blot and RT-PCR. Next, we treated Huh7 cells with sorafenib in combination with necroptosis inhibitor necrostatin-1. Necrostatin-1 attenuated the effect of sorafenib and increased the cell viability, which raises the possibility that necroptosis pathway is involved in the action mechanism of sorafenib.

Research Products

• [Journal Article] Sorafenib enhances proteasome inhibitor-induced cell death via inactivation of Akt and stress-activated protein kinases (2014)
  • Author(s): Honma Y, Shimizu S, Takehara T, Harada M
  • Journal Title: J Gastroenterol Volume: 49 Pages: 517-526
  • Peer Reviewed
• [Journal Article] Sorafenib enhances proteasome inhibitor-induced cell death via inactivation of Akt and stress-activated protein kinases. (2014)
  • Author(s): Honma Y, Shimizu S, Takehara T, Harada M.
  • Journal Title: J Gastroenterol. Volume: 49 Issue: 3 Pages: 517-526
  • DOI: 10.1007/s00535-013-0796-z
  • Peer Reviewed
• [Journal Article] The combination therapy of α-galactosylceramide and 5-fluorouracil showed antitumor effect synergistically against liver tumor in mice (2013)
  • Author(s): Aketa H, Tatsumi T, Kohga K, Tsunematsu H, Aono S, Shimizu S, Kodama T, Nawa T, Shigekawa M, Hikita H, Sakamori R, Hosui A, Miyagi T, Hiramatsu N, Kanto T, Hayashi N, Takehara T
  • Journal Title: Int J Cancer Volume: 133 Pages: 1126-1134
  • Peer Reviewed
• [Journal Article] The Bcl-2 Homology Domain 3 (BH3)-only Proteins Bim and Bid Are Functionally Active and Restrained by Anti-apoptotic 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 combination therapy of α-galactosylceramide and 5-fluorouracil showed antitumor effect synergistically against liver tumor in mice (2013)
  • Author(s): Aketa H, Tatsumi T, Kohga K, Tsunematsu H, Aono S, Shimizu S, Kodama T, Nawa T, Shigekawa M, Hikita H, Sakamori R, Hosui A, Miyagi T, Hiramatsu N, Kanto T, Hayashi N, Takehara T
  • Journal Title: Int J Cancer Volume: 133 Issue: 5 Pages: 1126-34
  • DOI: 10.1002/ijc.28118
  • Peer Reviewed
• [Journal Article] Valine, the branched-chain amino acid, suppresses hepatitis C virus RNA replication but promotes infectious particle formation (2013)
  • Author(s): Ishida H, Kato T, Takehana K, Tatsumi T, Hosui A, Nawa T, Kodama T, Shimizu S, Hikita H, Hiramatsu N, Kanto T, Hayashi N, Takehara T
  • Journal Title: Biochem Biophys Res Commun Volume: 437 Issue: 1 Pages: 127-33
  • DOI: 10.1016/j.bbrc.2013.06.051
  • Peer Reviewed
• [Journal Article] Carbamazepine promotes liver regeneration and survival in mice. (2013)
  • Author(s): Kawaguchi T, Kodama T, Hikita H, Tanaka S, Shigekawa M, Nawa T, Shimizu S, Li W, Miyagi T, Hiramatsu N, Tatsumi T, Takehara T.
  • Journal Title: J Hepatol. Volume: 59 Issue: 6 Pages: 1239-1245
  • DOI: 10.1016/j.jhep.2013.07.018
  • 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] 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] Interleukin-1β enhances the production of soluble MICA in human hepatocellular carcinoma. (2012)
  • Author(s): Kohga K, Tatsumi T, Tsunematsu H, Aono S, Shimizu S, Kodama T, Hikita H, Yamamoto M, Oze T, Aketa H, Hosui A, Miyagi T, Ishida H, Hiramatsu N, Kanto T, Hayashi N, Takehara T.
  • Journal Title: Cancer Immunol Immunother. Volume: 61 Pages: 1425-1432
  • 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] Mcl-1 and Bcl-xL regulate Bak/Bax-dependent apoptosis of the megakaryocytic lineage at multistages. (2012)
  • Author(s): Kodama T, Hikita H, Kawaguchi T, Shigekawa M, Shimizu S, Hayashi Y, Li W, Miyagi T, Hosui A, Tatsumi T, Kanto T, Hiramatsu N, Kiyomizu K, Tadokoro S, Tomiyama Y, Hayashi N, Takehara T.
  • Journal Title: Cell Death Differ. Volume: 19(11) Issue: 11 Pages: 1856-1869
  • DOI: 10.1038/cdd.2012.88
  • Peer Reviewed
• [Journal Article] Interferon-α suppresses hepatitis B virus enhancer II activity via the protein kinase C pathway (2012)
  • Author(s): Nawa T, Tatsumi T, et al.
  • Journal Title: Virology Volume: 432 Issue: 2 Pages: 452-459
  • DOI: 10.1016/j.virol.2012.07.002
  • Peer Reviewed
• [Journal Article] Pancreatitis STAT3 protects mice against caerulein-induced pancreatitis via PAP1 induction (2012)
  • Author(s): Shigekawa M, Tatsumi T, et al.
  • Journal Title: The American Journal of Pathology Volume: 181 Issue: 6 Pages: 2105-2113
  • DOI: 10.1016/j.ajpath.2012.08.038
  • 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
  • Place of Presentation: Washington, USA
• [Presentation] Hepatitis C virus infection reduces chemo-sensitivity of the hepatocellular carcinoma cells through enhancing cancer stem cell characters (2013)
  • Author(s): Takatoshi Nawa, Tomohide Tatsumi, Akira Nishio, Seiichi Tawara, Yoshiki Ohnishi, Satoshi Aono, Satoshi Shimizu, Hayato Hikita, 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] 肝細胞癌におけるCD26分子発現の意義 (2013)
  • Author(s): 川口司、疋田隼人、巽智秀、田中聡司、青野悟志、向井香織、清水聡、宮城琢也、友國晃、永野浩昭、土岐祐一郎、森正樹、竹原徹郎
  • Organizer: 第49回肝臓学会総会
  • Place of Presentation: 東京
• [Presentation] 大腸癌細胞のp53欠損は間質細胞進展に寄与する (2013)
  • Author(s): 林義人、辻井正彦、赤坂智史、重川稔、清水聡、疋田隼人、阪森亮太郎、新崎信一郎、宮城琢也、巽 智秀、竹原徹郎
  • Organizer: 第72回癌学会総会
  • Place of Presentation: 横浜
• [Presentation] 肝細胞癌におけるCD26分子発現の意義 (2013)
  • Author(s): 川口司、疋田隼人、巽智秀、田中聡司、青野悟志、向井香織、清水 聡、宮城琢也、友國晃、永野浩昭、土岐祐一郎、森 正樹、竹原徹郎
  • Organizer: 第４９回肝臓学会総会
  • Place of Presentation: 東京
• [Presentation] 進行肝細胞癌においてSTAT3シグナルは有用な治療ターゲットとなりうる (2013)
  • Author(s): 重川稔、疋田隼人、巽智秀、岩橋潔、池澤賢治、清水聡、阪森亮太郎、宮城琢也、平松直樹、竹原徹郎
  • Organizer: 第４９回肝臓学会総会
  • Place of Presentation: 東京
• [Presentation] 大腸癌細胞のp53欠損は間質細胞進展に寄与する (2013)
  • Author(s): 林義人、辻井正彦、赤坂智史、重川稔、清水聡、疋田隼人、阪森亮太郎、新崎信一郎、宮城琢也、巽智秀、竹原徹郎
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: 横浜
• [Presentation] Ras経路が活性化されている進行肝細胞癌におけるSTAT3シグナルの意義 (2013)
  • Author(s): 重川稔、疋田隼人、巽智秀、齋藤義修、清水聡、林義人、阪森亮太郎、宮城琢也、辻井正彦、竹原徹郎
  • Organizer: 第72回日本癌学会総会
  • Place of Presentation: 横浜
• [Presentation] Hepatitis C virus infection reduces chemo-sensitivity of the hepatocellular carcinoma cells through enhancing cancer stem cell characters. (2013)
  • Author(s): Takatoshi Nawa, Tomohide Tatsumi, Akira Nishio, Seiichi Tawara, Yoshiki Ohnishi, Satoshi Aono, Satoshi Shimizu, Hayato Hikita, 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.
• [Presentation] The impact of interferon therapy for chronic hepatitis C on methylation status in the liver (2012)
  • Author(s): Satoshi Shimizu, Tsugiko Oze, Minoru Shigekawa, Takahiro Kodama, Hayato Hikita, Takuya Miyagi, Atsushi Hosui, Harumasa Yoshihara, Tomohide Tatsumi, Tetsuo Takehara
  • Organizer: DDW2012
  • Place of Presentation: San Diego, USA
• [Presentation] IFN治療がC型肝炎の肝メチル化に与える影響について (2012)
  • Author(s): 清水聡、巽智秀、小玉尚宏、疋田隼人、宮城琢也、竹原徹郎
  • Organizer: 第71回癌学会総会
  • Place of Presentation: 札幌
• [Presentation] The impact of interferon therapy for chronic hepatitis C on methylation status in the liver.
  • Author(s): Satoshi Shimizu, Tsugiko Oze, Minoru Shigekawa, Takahiro Kodama, Hayato Hikita, Takuya Miyagi, Atsushi Hosui, Harumasa Yoshihara, Tomohide Tatsumi, Tetsuo Takehara
  • Organizer: DDW 2012
  • Place of Presentation: San Diego, CA, United States
• [Presentation] C型肝炎における肝メチル化の定量的評価
  • Author(s): 清水聡、小瀬嗣子、巽智秀、甲賀啓介、小玉尚宏、疋田隼人、宮城琢也、法水淳、吉原治正、竹原徹郎
  • Organizer: 第48回日本肝臓学会総会
  • Place of Presentation: ホテル日航金沢、金沢、日本
• [Presentation] The impact of interferon therapy for chronic hepatitis C on methylation status in the liver.
  • Author(s): Satoshi Shimizu, Tomohide Tatsumi, Takahiro Kodama, Hayato Hikita, Takuya Miyagi, Tetsuo Takehara
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌、札幌、日本
• [Remarks] ホームページ等 データ更新中
  • URL: http://www.med.osaka-u.ac.jp/pub/gh/research_a.html