title: Nuclear beta-catenin induces an early liver progenitor phenotype in hepatocellular carcinoma and promotes tumor recurrence.
abstract: 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.
authors.affiliation: Department of Internal Medicine I, Centre of Public Health, Medical University of Vienna, Vienna, Austria.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Zulehner
authors.forename: Mario
authors.initials: M
authors.lastname: Mikula
authors.forename: Doris
authors.initials: D
authors.lastname: Schneller
authors.forename: Franziska
authors.initials: F
authors.lastname: van Zijl
authors.forename: Heidemarie
authors.initials: H
authors.lastname: Huber
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sieghart
authors.forename: Bettina
authors.initials: B
authors.lastname: Grasl-Kraupp
authors.forename: Thomas
authors.initials: T
authors.lastname: Waldhör
authors.forename: Markus
authors.initials: M
authors.lastname: Peck-Radosavljevic
authors.forename: Hartmut
authors.initials: H
authors.lastname: Beug
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mikulits
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008113:Liver Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D016031:Liver Transplantation; D008297:Male; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000150:complications; D010641:Phenotype; D021381:Protein Transport; D015398:Signal Transduction; D051906:Smad7 Protein / Q000378:metabolism; D013234:Stem Cells / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D015820:Cadherins; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; D051176:beta Catenin