Modification of endoplasmic reticulum stress expands surgical indication in hepatocellular carcinom a

• Project/Area Number: 20591609
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kyoto University
• Principal Investigator: HATANO Etsuro Kyoto University, 医学研究科, 講師 (80359801)
• Co-Investigator(Kenkyū-buntansha): UEMOTO Shinji 京都大学, 医学研究科, 教授 (40252449) ; NITTA Takashi 京都大学, 医学研究科, 助教 (40456877) ; YASUCHIKA Kentaro 京都大学, 医学研究科, 助教 (00378895) ; IKAI Iwao 京都大学, 医学研究科, 准教授 (60263084)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2008: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 癌 / ストレス / アポトーシス / 肝細胞癌 / 小胞体ストレス / CHOP / GADD153 / JNK

Research Abstract

C/EBP homologous protein (CHOP) is one of the key components of the endoplasmic reticulum (ER) stress-mediated apoptosis. We investigated the role of CHOP in cholestatic liver injury. Liver fibrosis was attenuated in CHOP knockout mice after bile duct ligation (BDL). Both apoptotic and necrotic hepatocyte deaths were attenuated in CHOP deficient mice. Cholestasis induces CHOP -mediated ER stress and t riggers hepatocyte death. CHOP deficiency attenuates hepatocyte death and subsequent liver fibrosis. CHOP expression was enhanced in human liver cirrhosis and hepatocellular carcinoma. Furthermore, inhibition of c-Jun NH_2-terminal kinase switches Smad3 signaling from oncogenesis to tumor-suppression in rat hepatocellular carcinoma. Taken together, we expect that modification of ER stress expands surgical indication in hepatocellular carcinoma.

Research Products

• [Journal Article] Olprinone attenuates excessive shear stress through up-regulation of endothelial nitric oxide synthase in a rat excessive hepatectomy model. (2011)
  • Author(s): K Yamanaka, E Hatano, M Narito, et al.
  • Journal Title: Liver Transpl. Volume: 17 Pages: 60-69
  • Peer Reviewed
• [Journal Article] Inhibition of c-Jun NH_2-Terminal Kinase Switches Smad3 Signaling from Oncogenesis to Tumor-suppression in Rat Hepatocellular Carcinoma (2009)
  • Author(s): Nagata, H., Hatano, E., Tada, M., Murata, M., Kitamura, K., Asechi, H., Narita, M., Yanagida, A., Tamaki, N., Yagi, S., Ikai, I., Matsuzaki, K., Uemoto, S.
  • Journal Title: Hepatology 49(6) Pages: 1944-53
  • Peer Reviewed
• [Journal Article] Inhibition of c-Jun NH_2-Terminal Kinase Switches Smad3 Signaling from Oncogenesis to Tumor- suppression in Rat Hepato cellular Carcinoma (2009)
  • Author(s): Nagata, H., Hatano, E., Tada, M., et al.
  • Journal Title: Hepatology 49 Pages: 1944-1953
  • Peer Reviewed
• [Journal Article] A phosphodiesterase III inhibitor protects rat liver from sinusoidal obstruction syndrome through heme oxygenase-1 induction. (2009)
  • Author(s): Narita M., Hatano, E., Ikai, I., et al.
  • Journal Title: Ann Surg 249 Pages: 1397-1401
  • NAID: 120001479079
  • Peer Reviewed
• [Journal Article] Dai-kenchu-to attenuates rat sinusoidal obstruction syndrome by inhibiting the accumulation of neutrophils in the liver (2009)
  • Author(s): Narita M., Hatano, E., Tamaki, N., et al.
  • Journal Title: J Gastoroen Hepatol, 24
  • Peer Reviewed
• [Journal Article] CHOP-deficiency attenuates cholestasis-induced liver fibrosis by redcution of hepatocyte injury. (2008)
  • Author(s): Tamaki, N., Hatano, E., Taura, K., Tada, M., Kodama Y., Nitta, T., Iwaisako, K., Seo, S., Nakajima, A., Ikai, I., Uemoto, S.
  • Journal Title: Am J Physiol 294(2)
  • Peer Reviewed
• [Journal Article] CHOP-deficiency attenuates cholestasis-induced liver fibrosis by redcution of hepatocyte injury (2008)
  • Author(s): Tamaki, N., Hatano, E., Taura, K., et al.
  • Journal Title: Am J Physiol 294
  • Peer Reviewed
• [Journal Article] Loss of Sept4 exacerbates liver fibrosis through the dysregulation of hepatic stellate cells (2008)
  • Author(s): 54. Iwaisako, K., Hatano, E., Taura, K., et al
  • Journal Title: J Hepatol 49 Pages: 768-778
  • Peer Reviewed
• [Journal Article] Proliferative activity in hepatocellular carcinoma is closely correlated with glucose metabolism but not angiogenesis.
  • Author(s): K Kitamura, E Hatano, T Higashi, et al.
  • Journal Title: J Hepatology Volume: (印刷中)
  • Peer Reviewed
• [Presentation] JNKの肝発癌過程における分子標的意義- JNK阻害剤による肝細胞癌治療の可能性- (2009)
  • Author(s): 長田博光, 波多野悦朗, 阿世知弘行, 成田匡大, 柳田敦子, 玉置信行, 猪飼伊和夫, 松崎恒一, 上本伸二
  • Organizer: 第109回日本外科学会
  • Place of Presentation: 福岡
  • Year and Date: 2009-04-04
• [Presentation] JNKの肝発癌過程における分子標的意義-JNK阻害剤による肝細胞癌治療の可能性- (2009)
  • Author(s): 長田博光, 波多野悦朗, 阿世知弘行, 他
  • Organizer: 第109回日本外科学会
  • Place of Presentation: 福岡
  • Year and Date: 2009-04-04
• [Presentation] ラット肝癌モデルにおけるJNK阻害剤による抗腫瘍効果 (2008)
  • Author(s): 長田博光、波多野悦朗、多田正晴、阿世知弘行、成田匡大、柳田敦子、玉置信行、猪飼伊和夫、松崎恒一、上本伸二
  • Organizer: 第63回日本消化器外科学会定期学術総会
  • Place of Presentation: 札幌
  • Year and Date: 2008-07-17