Nuclear beta-catenin induces an early liver progenitor phenotype in hepatocellular carcinoma and promotes tumor recurrence.
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.
Zulehner
Gudrun
G
Department of Internal Medicine I, Centre of Public Health, Medical University of Vienna, Vienna, Austria.
Mikula
Mario
M
Schneller
Doris
D
van Zijl
Franziska
F
Huber
Heidemarie
H
Sieghart
Wolfgang
W
Grasl-Kraupp
Bettina
B
Waldhör
Thomas
T
Peck-Radosavljevic
Markus
M
Beug
Hartmut
H
Mikulits
Wolfgang
W
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*
D015820:Cadherins; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; D051176:beta Catenin