Stabilized beta-catenin promotes hepatocyte proliferation and inhibits TNFalpha-induced apoptosis

Lab Invest. 2004 Mar;84(3):332-41. doi: 10.1038/labinvest.3700043.

Abstract

The human hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The mechanisms of liver cell oncogenic transformation are still unknown. The beta-catenin mutations are identified in up to 30% of HCC and 80% of hepatoblastoma, suggesting a potential role of beta-catenin in the pathogenesis of liver cancers. To define the biological role of the stabilized beta-catenin in liver cell growth and transformation, we examined the effect of mutant beta-catenin on an immortalized murine hepatocyte cell line, AML12. A cell line that stably expresses mutant beta-catenin was established. The cell proliferation, apoptosis, and cell transformation of this cell line were characterized. Our data indicate that the stabilized beta-catenin enhances hepatocyte proliferation, suppresses TNFalpha/Act D-induced cell apoptosis, and causes weak anchorage-independent cell growth. The stabilized beta-catenin-containing cells did not develop tumor in immune-deficient mice. The target genes, c-myc and cyclin D1, were activated by beta-catenin in the hepatocytes. Our study suggests that mutant beta-catenin can promote cell proliferation and cell survival ability, but the stabilized beta-catenin alone is insufficient for completely oncogenic transformation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Carcinoma, Hepatocellular / etiology
  • Cell Division
  • Cell Line
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic
  • Cyclin D1 / genetics
  • Cytoskeletal Proteins / chemistry
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / physiology*
  • Drug Stability
  • Gene Expression Regulation
  • Genes, myc
  • Hepatocytes / cytology*
  • Hepatocytes / physiology*
  • Humans
  • Liver Neoplasms / etiology
  • Mice
  • Mice, SCID
  • Mutation
  • Trans-Activators / chemistry
  • Trans-Activators / genetics
  • Trans-Activators / physiology*
  • Transfection
  • Tumor Necrosis Factor-alpha / pharmacology
  • beta Catenin

Substances

  • CTNNB1 protein, human
  • CTNNB1 protein, mouse
  • Cytoskeletal Proteins
  • Trans-Activators
  • Tumor Necrosis Factor-alpha
  • beta Catenin
  • Cyclin D1