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Cross-talk of Ito(stellate) cell and preneoplastic and cancer cells of hepatocarcinogenesis

Research Project

Project/Area Number 11670507
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

SAKAIDA Isao  Yamaguchi University, School of Medicine, Lecturer, 医学部, 講師 (80263763)

Co-Investigator(Kenkyū-buntansha) OKITA Kiwamu  Yamaguchi University, School of Medicine, Professor, 医学部, 教授 (70107738)
Project Period (FY) 1999 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2002: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2001: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2000: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1999: ¥800,000 (Direct Cost: ¥800,000)
KeywordsStellate cell / Cancer cell / preneoplastic lesion / fibrosis / TGF-beta 1 / 伊藤細胞 / 癌 / 伊東細胞 / TGF-β / シグナル伝達
Research Abstract

Our finding during investigation terms are as follows ;
(1) Choline deficient L-amino acid (CDAA) defined diet induced hepatocyte cell death and regeneration resulting in stellate cell activation leading to preneoplastic lesions surrounded with fibrosis. Treatment with anti-fibrotic agent e.g. prolyl 4-hydrohylase inhibitor lead to the inhibition of stellate cell activation resulting in the prevention of preneoplastic lesions with reduced fibrosis without the protection of cell death.
(2) Treatment rats with Choline deficient L-amino acid (CDAA) defined diet induced the cell death and regeneration causing the activation of Kupffer and stellate cells which will produce TGF-beta 1 resulting in the perpetuation of fibrosis.
(3) Addition of the supernatant of cultured hepatic cancer cells on stellate cells induced activation of MAP kinase pathway but addition of the supernatant of stellate cells on cancer cells did not change the cell cycle of cancer cell. Co-culture of stellate cells and cancer cells indicated that the movement of stellate cells to cancer cells. This result may suggest the prevention of cancer cell invasion by stellate cells. However further studies are necessary.
(4) The activation of MAP kinase pathway by using adenovirus system revealed that the expression of MMP-9 is regulated mainly by ERK pathway and MMP-13 is regulated by P38 pathway independently.
These results will give the new insight for the therapy of liver fibrosis as well as the mechanism of cancer metastasis.

Report

(5 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • Research Products

    (25 results)

All Other

All Publications (25 results)

  • [Publications] Sakaida I: "Gadolinium chloride reverses dimethylnitrosamine (DMN)-induced rat liver fibrosis with increased matrix metalloproteinases (MMPs) of Kupffer cells"Life Science. 10. 943-959 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shirahashi H: "Ubiquitin is a possible new predictive marker for the recurrence of human hepatocellular carcinoma"Liver. 22. 413-418 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Segawa M: "Antioxidant, N-acetyl-L-cysteine inhibits the expression of the collagen alpha2 (I) promoter in the activated human hepatic stellate cell line in the absence as well as the presence of transforming growth factor-beta"Hepatology Research. 24. 305-315 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hironaka K: "Correlation between stellate cell activation and serum fibrosis markers in choline-deficient L-amino acid-defined diet-induced rat liver fibrosis"Digestive Disease & Science. 45. 1935-1943 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Aoyagi N: "Prolyl 4-hydroxylase inhibitor is more effective for the inhibition of proliferation than for inhibition of collagen synthesis of rat hepatic stellate cells"Hepatology Research. 23. 1-6 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sakaida I: "Loss of inhibitory growth regulation by TGF-beta1 in preneoplastic lesions in rat liver"Digestive Disease & Science. 45. 325-333 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sakaida I.: "Gadolinium chloride reverses dimethylnitrosamine (DMN)-induced rat liver fibrosis with increased matrix metalloproteinases (MMPs) of Kupffer cells"Life Sci.. 10. 943-959 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shirahashi H.: "Ubiquitin is a possible new predictive marker for the recurrence of human hepatocellular carcinoma"Liver. 22. 413-418 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Segawa M.: "Antioxidant, N-acetyl-L-cysteine inhibits the expression of the collagen alpha2 (I) promoter in the activated human hepatic stellate cell line in the absence as well as the presence of transforming growth factor-beta"Hepatol Res.. 24. 305 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hironaka K.: "Correlation between stellate cell activation and serum fibrosis markers in choline-deficient L-amino acid-defined diet-induced rat liver fibrosis"Dig Dis Sci. 45. 1935-1943 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Aoyagi M.: "Prolyl 4-hydroxylase inhibitor is more effective for the inhibition of proliferation than for inhibition of collagen synthesis of rat hepatic stellate cells"Hepatol Res.. 23. 1-6 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sakaida I.: "Loss of inhibitory growth regulation by TGF-beta1 in preneoplastic lesions in rat liver"Dig Dis Sci.. 45. 325-333 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sakaida I: "Gadolinium chloride reverses dimethylnitrosamine (DMN)-induced rat liver fibrosis with increased matrix metalloproteinases (MMPs) of Kupffer cells"Life Science. 10. 943-959 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Shirahashi H: "Ubiquitin is a possible new predictive marker for the recurrence of human hepatocellular carcinoma"Liver. 22. 413-418 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Segawa M: "Antioxidant, N-acetyl-L-cysteine inhibits the expression of the collagen alpha2 (I) promoter in the activated human hepatic stellate cell line in the absence as well as the presence of transforming growth factor-beta"Hepatology Research. 24. 305-315 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sakaguchi E: "Th1 down-regulation at the single-lymphocyte level in HCV-related liver cirrhosis and the effect of TGF-beta on Th1 response: possible implications for the development of hepatoma"Hepatology Research. 24. 282-289 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Aoyagi M: "Prolyl 4-hydroxylase inhibitor is more effective for the inhibition of proliferation than for inhibition of collagen synthesis of rat hepatic stellate cells"Hepatology Research. 23. 1-6 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Fukumoto Y: "Effects of secretin on TCDCA-or TDCA-induced cholestatic liver injury in the rat"Hepatology Research. 22. 214-222 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sakaida I et al.: "Characteristics of the cell proliferation profile of activated rat hepatic stellate cells in vitro in contrast to their fibrogenesis activity"J. Gastroenterol. 36(5). 322-329 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sakaida I, et al., : "Loss of inhibitory growth regulation by TGF-beta1 in preneoplastic lesions in rat liver."Dig Dis Sci.. 45. 325-333 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sakaida I, et al.,: "Correlation between stellate cell activation and serum fibrosis markers in choline-deficient L-amino acid-deflned diet-induced rat liver fibrosis."Dig Dis Sci. 45. 1935-1943 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sakaida I etal.: "Prolyl 4-hydroxylase inhibitor(HOE077) prevents TIMP-1 gene expression in rat liver fibrosis."J Gastroenterol. 34. 376-377 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Sakaida I et al.: "Long-term administration of heterogeneous interferon results in a loss of its biological effect."Liver. 19. 529-530 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Sakaida I et al.: "Loss of inhibitory growth regulation by TGF-β1 in preneoplastic lesions in rat liver."Dig.Dis.Sci.. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] Hironaka K,et al.: "Enhanced interstitial collagenase(matrix metalloproteinase-13) production of Kupffer cell by gadolinium chloride prevents pig serum-induced rat liver fibrosis in vivo."Biochem.Biophys.Res.Commun.. (in press).

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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