Dataset Information

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.

SUBMITTER: Zulehner G

PROVIDER: S-EPMC2797905 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Zulehner Gudrun G 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

The American journal of pathology 20091211 1

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 ...[more]

PMID: 20008139

Similar Datasets

Project description:Cancer stem cells (CSCs) are the key factor in determining cancer recurrence, metastasis, chemoresistance and patient prognosis in hepatocellular carcinoma (HCC). The role of miR-5188 in cancer stemness has never been documented. In this study, we investigated the clinical and biological roles of miR-5188 in HCC. Methods: MiRNA expression in HCC was analyzed by bioinformatics analysis and in situ hybridization. The biological effect of miR-5188 was demonstrated in both in vitro and in vivo studies through the ectopic expression of miR-5188. The target gene and molecular pathway of miR-5188 were characterized using bioinformatics tools, dual-luciferase reporter assays, gene knockdown, and rescue experiments. Results: MiR-5188 was shown to be upregulated and confer poor prognosis in HCC patient data from TCGA database. MiR-5188 was subsequently identified as a significant inducer of cancer stemness that promotes HCC pathogenesis. Specifically, the targeting of miR-5188 by its antagomir markedly prolonged the survival time of HCC-bearing mice and improved HCC cell chemosensitivity in vivo. Mechanistic analysis indicated that miR-5188 directly targets FOXO1, which interacts with β-catenin in the cytoplasm to reduce the nuclear translocation of β-catenin and promotes the activation of Wnt signaling and downstream tumor stemness, EMT, and c-Jun. Moreover, c-Jun transcriptionally activates miR-5188 expression, forming a positive feedback loop. Interestingly, the miR-5188-FOXO1/β-catenin-c-Jun feedback loop was induced by hepatitis X protein (HBX) through Wnt signaling and participated in the HBX-induced pathogenesis of HCC. Finally, analyses of transcriptomics data and our clinical data supported the significance of the abnormal expression of the miR-5188 pathway in HCC pathogenesis. Conclusions: These findings present the inhibition of miR-5188 as a novel strategy for the efficient elimination of CSCs to prevent tumor metastasis, recurrence and chemoresistance in patients with hepatocellular carcinoma. Our study highlights the importance of miR-5188 as a tumor stemness inducer that acts as a potential target for HCC treatment.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets