Stabilized beta-catenin promotes hepatocyte proliferation and inhibits TNFalpha-induced apoptosis.
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.
Shang
Xian-Zhang
XZ
Department of Pathology, Immunology and Laboratory Medicine, University of Florida, P.O. Box 100275, Gainesville, FL 32610, USA.
Zhu
Haizhen
H
Lin
Karrie
K
Tu
Zhengkun
Z
Chen
Jisheng
J
Nelson
David R
DR
Liu
Chen
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000209:etiology; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D019938:Cyclin D1 / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D004355:Drug Stability; D005786:Gene Expression Regulation; D016259:Genes, myc; D022781:Hepatocytes / Q000166:cytology* / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin; D019938:Cyclin D1