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Analyses of TGF-β Signal Transduction Mechanisms in Hepatocellular Carcinoma and Applications for its Treatment.

Research Project

Project/Area Number 11670546
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionKansai Medical University

Principal Investigator

MATSUZAKI Koichi  Kansai Medical University Third Department of Internal Medicine Assistant Professor, 医学部, 講師 (70278638)

Co-Investigator(Kenkyū-buntansha) NAKAHASHI Yoshitsugu  Kansai Medical University Third Department of Internal Medicine Research Assistant, 医学部, 助手 (70247930)
SEKI Toshihito  Kansai Medical University Third Department of Internal Medicine Associate Professor, 医学部, 助教授 (70163087)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2000: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1999: ¥2,900,000 (Direct Cost: ¥2,900,000)
KeywordsHepatocellular Carcinoma / TGF-β / Smad / TGF-β受容体 / アクチビン
Research Abstract

To clarify the mechanism of resistance to the anti-proliferative effect of TGF-b in human HCC cells, we studied the stimulatory mechanism by tumor-derived TGF-β using HCC-M and HCC-T cell lines. In these cells, tumor-derived TGF-β accelerated their proliferation. Smad 2 was constitutively activated by the autocrine mechanism. This constitutive activation of Smad 2 was, at least in part, due to the lack of induction of antagonistic Smads by TGF-β (Cancer Res. 2000 ; 60 : 1394-1402). Furthermore, we investigated regulatory mechanisms for TGF-β as an autocrine inhibitor using HuH-7 and HepG2 cells. The study demonstrated that HuH-7 and HepG2 cells exhibited only a limited growth inhibitory response to TGF-β in comparison with hepatocytes, because tumor-derived TGF-β induced antagonistic Smad 7, and Smad 7 limited the basal activation levels of R-Smads (Hepatology 2000 ; 32 : 218-227).
We also showed that Down-regulation of TGF-β receptor occurred in hepatocytes after chemical insult and TGF-β could not transduce its anti-proliferative signal. Recovery of TGF-β receptor expression causes the signal to transduce to the nucleus at 72 hr. In HSC, whenever TGF-β is increased, TGF-β can transduce its signal for fibronectin production via its receptor, because signaling receptors are expressed constantly (Gut 2000 ; 46 : 719-724, J of Hepatology 2000 ; 32 : 251-260, J of Hepatology 1998 ; 28 : 572-581).

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report

Research Products

(25 results)

All Other

All Publications (25 results)

  • [Publications] Matsuzakik.,Date M. et al.: "Regulatory Mechanisms for TGF-β as Autocrine Inhibitor in Human Hepatocellular Carcinoma : Implications of Roles of Smads in Its Growth"Hepatology. 32. 218-227 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsuzakik.,Date M. et al.: "Autocrine Stimulator Mechanism by TGF-β in Human Hepatocellular Carcinoma"Cancer Research. 60. 1394-1402 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Date M.,Matsuzaki K. et al.: "Modulation of Transforming Growth Factor-βFunction in Hepatcytes and Hepatic Stellate Cells in Rat Liver Iniury"Gut. 46. 719-724 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Date M.,Matsuzaki K et al.: "Differential Regulation of Activin A Siqual Transaction in Hepatocytes and Hepatic Stellate Cells of Rat liver Injury."Journal of Hepatology. 32. 251-260 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsushita M.,Matsuzaki M. et al.: "Down-requlation of TGF-β receptors in Human Colorectal Cancer : Implications for Cancer Development."British Journal of Cancer. 80(1/2). 194-205 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Date M.,Matsuzaki K. et al.: "Differential Expression of Transforming Growth Factor-β Receptors in Hepatocytes and Nonparenchymal Cells of Rat Liver Injury."Journal of Hepatology. 28. 572-581 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsuzaki K, Date M., Furukawa F., Tahashi Y., Matsushita M., Sugano Y., Yamashiki N., Nakagawa T., Seki T., Nishizawa M., Fujisawa J., Inoue K.: "Regulatory Mechanisms for TGF-β as Autocrine Inhibitor in Human Hepatocellular Carcinoma : Implications for Roles of Smads in Its Growth."Hepatology.. 32. 218-227 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsuzaki K, Date M., Furukawa F., Tahashi Y., Matsushita M., Sakitani K., Yamashiki N., Seki T., Saito H., Nishizawa M., Fujisawa J., Inoue K.: "Autocrine Stimulatory Mechanism by TGF-β in Human Hepatocellular Carcinoma."Cancer Res.. 60. 1394-1402 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Date M, Matsuzaki K, Matsushita M, Tahashi Y, Furukawa F, Sakitani K, Inoue K.: "Modulation of Transforming Growth Factor-β Function in Hepatocytes and Hepatic Stellate Cells in Rat Liver Injury."Gut. 46. 719-724 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Date M, Matsuzaki K, Matsushita M, Tahashi Y, Sakitani K, Inoue K.: "Differential Regulation of Activin A Signal Transduction in Hepatocytes and Hepatic Stellate Cells of Rat Liver Injury."Journal of Hepatology. 32. 251-260 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsushita M, Matsuzaki K, Date M, Watanabe T, Shibano K, Nakagawa T, Yanagitani S, Amoh Y, Ogata N, Yamamoto C, Kubota T, Seki T, Inokuchi H, Nishizawa M, Takada H, Sawamura T, Okamura A, Inoue K.: "Down-regulation of TGF-β receptors in Human Colorectal Cancer : Implications for Cancer Development."British Journal of Cancer. 80 (1/2). 194-205 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Date M., Matsuzaki K., Matsushita M., Sakitani K., Okajima A., Shibano K., Yamamoto C., Ogata N., Okumura T., Seki T., Kubota T., Kan M., McKeehan W.L.and Inoue K.: "Differential Expression of Transforming Growth Factor-β Receptors in Hepatocytes and Nonparenchymal Cells of Rat Liver Injury"Journal of Hepatology. 28. 572-581 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsuzaki K.,Date M. et al: "Regulatory Mechanisms for TGF-βas Autocrine Inhibitor in Human Hepatocellular Carcinoma : Implications for Rolos of Smads in its Growth"Hepatology. 32. 218-227 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Matsuzaki K.,Date M. et al: "Aitocine Sturlatory Mechanism by TGFβ in human Hepatocellular Carcinoma"Carcer Research. 60. 1394-1402 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Date M.,Matsuzaki K., et al: "Modulation of Transforming Growth Factor-βFunction in Hepatoaites and Hepatic Sollate Cells in Rat Liver Injury"Gut. 46. 719-724 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Date M.,Matsuzaki K., et al: "Differential Regulation of Actirin A Signal Tranduation in Hepatoriter and Hepatic Sollate Cells of Rat Liver Injury"Journal of Hepatology. 32. 251-260 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Matsushita M.,Matsuzaki K., et al: "Down-regulation of TGF-βreceptors in Human Coloractal Cancer : Implications for Cancer Development"British Journal of Cancer. 80(1/2). 194-205 (1999)

    • Related Report
      2000 Annual Research Report
  • [Publications] Date M.,Matsuzaki K., et al: "Differential Expression of Transforming Growth Factor-βReceptors in Hepatoaites and Nonparenchymal Cells of Rat Liver Injury"Journal of Hepatology. 28. 572-581 (1998)

    • Related Report
      2000 Annual Research Report
  • [Publications] Koichi Matsuzaki: "Autocrine Stimulatory mechanism by TGF-β in human hepatocellular carcinoma"Cancer Research. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Masataka Date: "Modulation of TGF-β function in hepatocytes and Hepatic stellate cells in rat live injury"Gut. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Masataka Date: "Differential Regulation of Activin A signal transduction in hepatocytes and hepatic stellate cells of rat live injury"Journal of Hepatology. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Masanori Matsushita: "Transcriptional down-regulation of TGF-β receptors in human colorectal cancer Implications for cancer development"British Journal of Cancer. 80(1/2). 194-205 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Masataka Date: "Differential expression of TGF-β receptors in hepatocytes and non parenchymal cells of rat liver injury"Journal of Hepatology. 28. 572-581 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Akiyoshi Taniguchi: "Ligand-dependent and independent interactions with the TGF-β type I and II receptor subunits reside in the amino terminal portion of the ectodomain of the type III subunit"In vitro Cell. Dev. Biol. Anim. 34. 232-238 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] 松崎 恒一: "肝胆膵"国際医書出版. 4 (1998)

    • Related Report
      1999 Annual Research Report

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Published: 1999-03-31   Modified: 2016-04-21  

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