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Anticancer therapy against hepatocellular carcinoma by survivin targeting

Research Project

Project/Area Number 13670531
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionNagasaki University

Principal Investigator

NAKAO Kazuhiko  Health Research Center, Associate professor, 保健管理センター, 助教授 (00264218)

Co-Investigator(Kenkyū-buntansha) ISHII Nobuko  Health Research Center, Professor, 保健管理センター, 教授 (20088868)
中田 恵輔  長崎大学, 医学部, 助教授 (40217740)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsSurvivin / Interferon-α / Hepatoma / TRAIL / siRNA / 樹状細胞 / survivin / DNAワクチン / 肝癌 / TIAP遺伝子
Research Abstract

Survivin, which is expressed in cancer tissues including hepatocellular carcinoma but not in normal tissues, represses the activities of caspases resulting in resistance of cancer cells to Fas- or chemotherapeutic agent-mediated apoptosis. In addition, inhibition of survivin expression, by transduction with anti-sense oligonucleotides or a dominant-negative expression vehicle, sensitized cancer cells to chemotherapeutic agent-mediated apoptosis. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, induces apoptosis in a variety of cancer cells with little or no effect on normal cells. Human hepatoma cells, however, are resistant to TRAIL-induced apoptosis. Recently, Griffith et al. reported that the cellular level of survivin is closely relevant to the resistance against TRAIL-mediated apoptosis of renal cell carcinoma cells. In the present study, we have shown that the preincubation with 1,000 IU of IFN-α apparently enhanced the TRAIL-induced apoptosis in HuH-7, Hep3B and PLC/PRF/5 human hepatoma cells. The expression of survivin as well as its m-RNA was repressed by IFN-α in these cells. We also demonstrated that ectopic expression of survivin significantly repressed the TRAIL/IFN-α -induced apoptosis of HuH-7 cells. These findings suggest that downregulation of survivin by IFN-α may account for the enhancement of TRAIL-mediated apoptosis by IFN-α, and that TRAIL in combination with IFN-α may have therapeutic potential in the treatment of human hepatocellular carcinoma.
We also found that down regulation of surviving expression by siRNA transfection sensitized human hepatoma cells to TRAIL-induced apoptosis.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (10 results)

All Other

All Publications (10 results)

  • [Publications] Hiroyuki Ishikawa, et al.: "Retrovirus-mediated gene therapy for hepatocellular carcinoma with reversely oriented therapeutic gene expression regulated by α-fetoprotein enhancer/promoter"Biochem.Biophys.Res.Commun.. 287. 1034-1040 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoko Tamada, et al.: "p48 overexpression enhances interferon-mediated expression and activity of double-stranded RNA-dependent protein kinase in human hepatoma cells"Journal of Hepatology. 37. 493-499 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Masaya Shigeno, et al.: "Interferon-α sensitizes human hepatoma cells to TRAIL-induced apoptosis through DR5 upregulation and NF-κB inactivation"Oncogene. 22. 1653-1662 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hiroki Ishikawa, Keisuke Nakata, Fumihiro Mawatari, Toshihito Ueki, Shotaro Tsuruta, Akio Ido, Kazuhiko Nakao, Yuji Kato, Nobuko Ishii, Katsumi Eguchi.: "Retrovirus-mediated gene therapy for hepatocellular carcinoma with reversely oriented therapeutic gene expression regulated by α-fetoprotein enhancer/promoter"Biochemical and Biophysical research communication. 287(4). 1034-1040 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoko Tamada, Kazuhiko Nakao, Yuji Nagayama, Keisuke Nakata, Tatsuki Ichikawa, Yosei Kawamata, Hiroki Ishikawa, Keisuke Hamasaki, Katsumi Eguchi, Nobuko Ishii.: "p48 overexpression enhances interferon-mediated expression and activity of double-stranded RNA-dependent protein kinase in human hepatoma cells"Journal of Hepatology. 37(4). 493-499 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Masaya Shigeno, Kazuhiko Nakao, Tatsuki Ichikawa, Kasumi Suzuki, Atsushi Kawakami, Seigou Abiru, Seiji Miyazoe, Yuichi Nakagawa, Hiroki Ishikawa, Keisuke Hamasaki, Keisuki Nakata, Nobuko Ishii, Katsumi Eguchi: "Interferon-α sensitizes human hepatoma cells to TRAIL-induced apoptosis through DR5 upregulation and NF-κB inactivation"Oncogene. 22(11). 1653-1662 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hiroki Ishikawa, et al.: "Retrovirus-mediated gene therapy for hepatocellular carcinoma with reversely oriented therapeutic gene expression regulated by α-fetoprotein enhancer/promoter"Biochem Biophys Res Commun. 287・4. 1034-1040 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yoko Tamada, et al.: "p48 overexpression enhances interferon-mediated expression and activity of double-stranded RNA-dependent protein kinase (PKR) in human hepatoma cells"Journal of Hepatology. 37・4. 493-499 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Masaya Shigeno, et al.: "Interferon-α sensitizes human hepatoma cells to TRAIL-induced apoptosis through DR5 upregulation and NF-κB inactivation"Oncogene. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hiroki Ishikawa, et al.: "Retrovirus-mediated gene therapy for hepatocellular carcinoma with reversely oriented therapeutic gene expression regulated by α-fetoprotein enhancer/promoter"Biochem Biophys Res Commun. 287・4. 1034-1040 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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