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Analysis of expressional changes of liver enriched transcription factors during occurrence and development of hepatocellular carcinoma, its application to pathological diagnosis and gene therapy

Research Project

Project/Area Number 10470049
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section一般
Research Field Human pathology
Research InstitutionKobe University

Principal Investigator

YOSHITAKE Hayashi  Kobe University School of Medicine. Pathology I, Associate Professor, 医学部, 助教授 (50189669)

Co-Investigator(Kenkyū-buntansha) MATOZAKI Takashi  Gumma University Institute for Molecular and Cellular Regulation. Biosignal Research Center, Professor, 生体調節研究所, 教授 (80252782)
SANO Kimihiko  Kobe University School of Medicine. Pediatrics, Lecturer, 医学部, 講師 (40205993)
穀内 隆  神戸大学, 医学部附属病院, 講師 (30178248)
Project Period (FY) 1998 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥10,900,000 (Direct Cost: ¥10,900,000)
Fiscal Year 2000: ¥100,000 (Direct Cost: ¥100,000)
Fiscal Year 1999: ¥100,000 (Direct Cost: ¥100,000)
Fiscal Year 1998: ¥10,700,000 (Direct Cost: ¥10,700,000)
KeywordsHNF-1 / HNF-4 / Transcription factor / Hepatocellular carcinoma / Pathology / Nuclear protein / Tyrosine phosphatase / SAP-1 / hepatocellular carcinoma / gene therapy / transcriptional regulation / pathology / differentiation / liver / HNF-3 / HNF-6 / E-cadherin / 肝細胞癌 / 転写制御因子 / 組織病理学
Research Abstract

Several liver enriched transcription factors were identified and the regulation of their expressions has been well known. We showed that HNF-1a expression decreased, although HNF-1β remained unchanged, during dedifferentiation from well differentiated hepatocellular carcinoma (HCC) to poorly differentiated HCC.We also characterized an undifferentiated HCC cell-line, referred to as ETK-1, which has the potency of bilateral differentiation, like liver stem cell, into both hepatocyte, referred to as MEK, and biliary epithelial cell, referred to as NEC.ETK-1 cell expressed neither HNF-1α nor HNF-4. MEK cell showed expression of both HNF-1α and HNF-4. NEC expressed only HNF-4, but not HNF-1α. ETK-1 and NEC had no expression of liver specific genes, such as transthyretin and albumin, AFP and so on, although MEK expressed all sets of liver specific genes. Our study focused on the mechanism how NEC has no expression of liver specific genes or HNF-1α in spite of its expression of HNF-4. Fluores … More cent microscopic observations of NEC cell demonstrated that the HNF-4 located in the cytoplasm, not in the nucleus. The lack of transference of HNF-4 from cytoplasm into nucleus seemed to induce its functional defect as a transcription regulator. Such abnormal distribution of nuclear transcription factors might be an important process in dedifferentiation of HCC.We also analysed the signal transduction molecules inplicated in liver enriched transcription regulation during dedifferentiation of HCC.Immunohistochemical and western- and northern-blot analysis of surgically hepatectomized HCC tissues showed that overexpression of SAP-1, a human transmembrane-type protein tyrosine phosphatase in well differentiated HCC and its expression decreased during dedifferentiation of HCC.Induction of overexpression of SAP-1 in poorly differentiated HCC cell-line by transgene caused redifferentiation of HCC, and suppressed cellular proliferation and invasion. SAP-1 may be a molecule implicated in evolution and metastasis of HCC through hepatocytic differentiation. Less

Report

(4 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (32 results)

All Other

All Publications (32 results)

  • [Publications] 二宮俊明,林祥剛: "肝細胞癌の組織分化における肝特異転写制御因子HNF-1α、HNF-1βの発現に関する研究"肝臓. 39. 298-300 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hayashi Y et al.: "The Liver-Enriched Transcription Factors and Differentiation of Human Hepatocellular Carcinoma"J Clin Pathol (Molec Pathol). 52. 19-24 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 林祥剛: "病理組織形態に反映する転写制御因子-肝細胞特異核蛋白発現の肝癌診断、治療への応用"病理と臨床. 17. 272-272 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Fukunaga K et al.: "Requirement for protein tyrosine phosphatase SHP-2 in insulin-induced activation of c-jun NH3-terminal kinase"J Biol Chem. 275. 5208-5213 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ninomiya T et al.: "Significance of serum matrix metalloproteinases and their inhibitors on the antifibrogenetic effect of interferon alfa in chronic hepatitis C patients"Intervirology. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ikawa H et al.: "Various scoring systems evaluating histological features of chronic hepatitis C after IFN therapy"Human Pathol. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Hayashi Y, Wang W, Ninomiya T, Nagano H, Ohta K, Itoh H.: "Invited Review Article. The Liver-Enriched Transcription Factors and Differentiation of Human Hepatocellular Carcinoma"Molec Pathol. 52(1). 19-24 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Morita Y, Hayashi Y, Kanamaru T, Itoh T, Suzuki S, Yamamoto M, Kuroda Y, Itoh H: "Inhibitory Role of Plasminogen Activator Inhibitor-1 in Invasion and Proliferation of HLE, Hepatocellular Carcinoma Cells"Jpn J Cancer Res. 90. 747-752 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Azumi H, Inoue N, Takeshita S, Rikitake Y, Kawashima S, Hayashi Y, Itoh H, Yokoyama M: "Expression of NADH/NADPH Oxidase p22phox in human coronary artery"Circulation. 100. 1494-1498 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Fukunaga K, Noguchi T, Takeda H, Matozaki T, Hayashi Y, Itoh H, Kasuga M.: "Requirement for protein tyrosine phosphatase SHP-2 in insulin-induced activation of c-jun NH_3-terminal kinase"J Biol Chem. 275. 5208-5213 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Zhou L, Hayashi Y, Itoh T, Wang W, Rui JA, Itoh H.: "Expression of Urokinase-Type Plasminogen Activator, Urokinase-Type Plasminogen Activator Receptor, Plasminogen Activator Inhibitor-1 and -2 in Hepatocellular Carcinoma"Pathology International. 50. 392-397 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Itoh T, Hayashi Y, Kanamaru T, Morita Y, Suzuki S, Wang W, Zhou L, Rui JA, Yamamoto M, Kuroda Y, Itoh H.: "Clinical Significance of Urokinase-type Plasminogen Activator Activity in Hepatocellular Carcinoma"J Gastroenterol Hepatol. 15. 422-430 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Wong N, Lai P, Pang E, Fung LF, Sheng Z, Wong V, Wang WP, Hayashi Y, Perlman E, Yuna S, Lau JWY, Johnson PJ.: "Genomic aberrations in human hepatocellular carcinomas of differing etiologies"Clinical Cancer Res. 6. 4000-4009 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Ikawa H, Hayashi Y, Ninomiya T, Yano Y, Nakaji M, Nagano H, Seo Y, Kumon Y, Yoon S, Kasuga M, Itoh H.: "Various scoring systems evaluating histological features of chronic hepatitis C after IFN therapy"Human Pathol. in press.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Fukunaga K et al.: "Requirement for protein tyrosine phosphatase SHP-2 in insulin-induced activation of c-jun NH3-terminal kinase"J Biol Chem. 275. 5208-5213 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Zhou L et al: "Expression of Urokinase-Type Plasminogen Activator, Urokinase-Type Plasminogen Activator Inhibitor-1 and-2 in Hepatocellular Carcinoma"Pathology International. 50. 392-397 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Itoh T et al.: "Clinical Significance of Urokinase-type Plasminogen Activator Activity in Hepatocellular Carcinoma"J Gastroenterol hepatol. 15. 422-430 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Wong N et al.: "Genomic aberrations in human hepatocellular carcinomas of differing etiologies"Clinical Cancer Res. 6. 4000-4009 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Ninomiya T et al.: "Significance of serum matrix metalloproteinases and their inhibitors on the antifibrogenetic effect of interferon alfa in chronic hepatitis C patients"Intervirology. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Ikawa H et al.: "Various scoring systems evaluating histological features of chronic hepatitis C after IFN therapy"Human Pathol. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Kim SR et al.: "TTV positivity and transfusion history in non-B and non-C HCC compared with HBV- and HCV- positive cases Intervirology in press"Intervirology. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] Itoh T et al.: "Clinical Significance of Urokinase-type Plasminogen Activator Activity in Hepatocellular Carcinoma"J Gastroenterol Hepatol. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] Zhou L et al.: "Expression of Urokinase-Type Plasminogen Activator,Urokinase-Type Plasminogen Activator Receptor,Plasminogen Activator Inhibitor-1 and -2 in Hepatocellular Carcinoma"Pathology International. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] Ninomiya T et al.: "Improvement of The Molar Ratio of Branched-Chain Amino Acids to Tyrosine(BTR) Associated with LiverFibrosis in Chronic Hepatitis C Patlents Treated with Interferon-α"Digestive Diseases and Sciences. 44. 1027-1033 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Morita Y et al.: "Inhibitory Role of Plasminogen Activator Inhibitor-1 in Invasion and Proliferation of HLE,HepatocellularCarcinoma Cells"Jpn J Cancer Res. 90. 747-752 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Hayashi Y et al.: "Invited Review Article.The Liver-Enriched Transcriptlon Factors and Differentiation of Human Hepatocellular Carcinoma"J Clin Pathol(Molec Pathol). 52(1). 19-24 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 林 祥剛: "病理組織形態に反映する転写制御因子-肝細胞特異核蛋白発現の肝癌診断、治療への応用" 病理と臨床. (印刷中).

    • Related Report
      1998 Annual Research Report
  • [Publications] Weiping Wang: "Expression of HNF-1α and HNF-1β in Various Histological Differentiations of Hepatocellular Carcinoma" J Pathol. 184. 272-278 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kentaro Kawasaki: "Developmental expression of the tight junction protein Occludin in the gastrointestinal tract in the chick embryo" Histochem Cell Biol. 109. 19-24 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Kentaro Kawasaki: "Expression of urokinase plasminogen activator receptor(uPAR)and plasminogen activator inhibitor-1(PAI-1)in the gastric cancer" J Gastroenterol Hepatol. 13. 892-896 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Satoshi Suzuki: "Expression of receptor for urokinase plasminogen activator in colorectal adnomas and carcinomas" GUT. 43. 798-805 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yoshitake Hayashi: "Review The Liver-Enriched Transcription Factors and Differentiation of Human Hepatocellular Carcinoma" J Clin Pathol: Molec Pathol. 52. 19-24 (1999)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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