Nuclear beta-catenin induces an early liver progenitor phenotype in hepatocellular carcinoma and promotes tumor recurrence

Am J Pathol. 2010 Jan;176(1):472-81. doi: 10.2353/ajpath.2010.090300. Epub 2009 Dec 11.


Transforming growth factor-beta cooperates with oncogenic Ras to activate nuclear beta-catenin during the epithelial to mesenchymal transition of hepatocytes, a process relevant in the progression of hepatocellular carcinoma (HCC). In this study we investigated the role of beta-catenin in the differentiation of murine, oncogene-targeted hepatocytes and in 133 human HCC patients scheduled for orthotopic liver transplantation. Transforming growth factor-beta caused dissociation of plasma membrane E-cadherin/beta-catenin complexes and accumulation of nuclear beta-catenin in Ras-transformed, but otherwise normal hepatocytes in p19(ARF)-/- mice. Both processes were inhibited by Smad7-mediated disruption of transforming growth factor-beta signaling. Overexpression of constitutively active beta-catenin resulted in high levels of CK19 and M2-PK, whereas ablation of beta-catenin by axin overexpression caused strong expression of CK8 and CK18. Therefore, nuclear beta-catenin resulted in dedifferentiation of neoplastic hepatocytes to immature progenitor cells, whereas loss of nuclear beta-catenin led to a differentiated HCC phenotype. Poorly differentiated human HCC showed cytoplasmic redistribution or even loss of E-cadherin, suggesting epithelial to mesenchymal transition. Analysis of 133 HCC patient samples revealed that 58.6% of human HCC exhibited strong nuclear beta-catenin accumulation, which correlated with clinical features such as vascular invasion and recurrence of disease after orthotopic liver transplantation. These data suggest that activation of beta-catenin signaling causes dedifferentiation to malignant, immature hepatocyte progenitors and facilitates recurrence of human HCC after orthotopic liver transplantation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cadherins / metabolism
  • Carcinoma, Hepatocellular / blood supply
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology*
  • Cell Differentiation
  • Cell Membrane / metabolism
  • Cell Nucleus / metabolism*
  • Epithelium / metabolism
  • Epithelium / pathology
  • Female
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Humans
  • Liver / metabolism
  • Liver / pathology*
  • Liver Neoplasms / blood supply
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology*
  • Liver Transplantation
  • Male
  • Mesoderm / metabolism
  • Mesoderm / pathology
  • Mice
  • Neoplasm Recurrence, Local / metabolism*
  • Neovascularization, Pathologic / complications
  • Phenotype
  • Protein Transport
  • Signal Transduction
  • Smad7 Protein / metabolism
  • Stem Cells / pathology*
  • Transforming Growth Factor beta / metabolism
  • beta Catenin / metabolism*


  • Cadherins
  • Smad7 Protein
  • Transforming Growth Factor beta
  • beta Catenin