Identification of Interferon Responsive Apoptosis Regulating Genes in Hepatocellular Carcinoma

• Project/Area Number: 16590632
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Keio University
• Principal Investigator: HIGUCHI Hajime Keio University, Department of Medicine, Instructor, 医学部, 助手 (20306682)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000); Fiscal Year 2004: ¥2,300,000 (Direct Cost: ¥2,300,000)
• Keywords: interferon / hepatocellular carcinoma / cyclooxygenase-2 / TRAIL / Death Receptor / apoptosis / caspase / interferon

Research Abstract

We identified that cyclooxygenase (COX)-2 gene is markedly upregulated in hepatocellular carcinoma (HCC) cells in response to interferon-beta treatment. Anti-apoptotic function of COX-2 is crucial in HCC cell apoptosis resistance. Apoptosis was identified by 4',6-diamidino-2-phenylindole dihydrochloride (DAPI) and fluorescent staining. IFN-β could up-regulate the expression of TRAIL, while NS-398 increased the expression of TRAIL receptors (especially of death receptor 5). Subsequently, activation of caspase-8 and caspase-3 was observed following the treatment with NS-398 and IFN-β in HepG2 cells. Blockade of TRAIL abrogated cell death induced by a combination of NS-398 and IFN-β in both HepG2 and HuH7 cells. Co-treatment with prostaglandin E2 partially abrogated NS-398+IFN-β-induced cell death in HuH7 cells, but not in HepG2 cells. Furthermore, in vivo experiment showed the combined regimen with NS-398 and IFN-β could reduce the growth of xenotransplated HCCs in nude mice. In conclusion, NS-398 is sufficient to overcome IFN resistance in hepatoma cells through the TRAIL/TRAIL receptor and COX-2 signaling pathway, therefore, the combination would appear to be an new therapeutic regimen for HCC.

Research Products

• [Journal Article] Cyclooxygenase (COX)-2 inhibitor and interferon-beta synergistically induce apoptosis in human hepatoma cells in vitro and in vivo (2006)
  • Author(s): Nobuhiro Nakamoto, Hajime Higuchi, Hideaki Kanamori, Hitomi Horikawa, Satoshi Kurita, Tetsuya Masuda, Shinichiro Tada, Hiromasa Takaishi, Kyoko Toda, Takaya Yamada, Naoki Kumagai, Hidetsugu Saito, Toshifumi Hibi
  • Journal Title: Int-J-Cancer (印刷中)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cyclooxygenase (COX)-2 inhibitor and interferon-beta synergistically induce apoptosis in human hepatoma cells in vitro and in vivo (2006)
  • Author(s): Nobuhiro Nakamoto, Hajime Higuchi, Hideaki Kanamori, Hitomi Horikawa, Satoshi Kurita, Tetsuya Masuda, Shinichiro Tada, Hiromasa Takaishi, Kyoko Toda, Takaya Yamada, Naoki Kumagai, Hidetsugu Saito, Toshifumi Hibi
  • Journal Title: Int J Cancer (In Press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cyclooxygenase (COX)-2 inhibitor and interferon-beta synergistically induce apoptosis in human hepatoma cells in vitro and in vivo
  • Author(s): Nobuhiro Nakamoto, Hajime Higuchi, Hideaki Kanamori, Hitomi Horikawa, Satoshi Kurita, Tetsuya Masuda, Shinichiro Tada, Tiromasa Takaishi, Kyoko Toda, Takaya Yamada, Naoki Kumagai, Hidetsugu Saito, Toshifumi Hibi
  • Journal Title: Int-J-Cancer (投稿中)(印刷中)