Activation of hepatic stem cell marker EpCAM by Wnt-beta-catenin signaling in hepatocellular carcinoma.

@article{citeulike:2955054, abstract = {The heterogeneous nature of hepatocellular carcinoma (HCC) and the lack of appropriate biomarkers have hampered patient prognosis and treatment stratification. Using a gene expression profiling approach, we recently identified a novel prognostic HCC subtype that resembles hepatic progenitor cells with the activation of stem cell markers and Wnt-beta-catenin signaling, based on EpCAM (epithelial cell adhesion molecule, a hepatic stem cell marker) expression. In this study, we investigated whether the activation of the Wnt-beta-catenin pathway regulates EpCAM expression. We found that nuclear accumulation of beta-catenin induced, whereas the degradation of beta-catenin or inhibition of Tcf/beta-catenin complex formation reduced EpCAM gene expression in cultured normal human hepatocytes and HCC cell lines. We identified two Tcf binding elements in the EpCAM promoter that specifically bound to Tcf-4 in an electrophoretic mobility shift assay. EpCAM promoter luciferase activity was down-regulated by the degradation of beta-catenin or inhibition of Tcf/beta-catenin complex formation. Furthermore, we found that EpCAM-positive HCC is much more sensitive to Tcf/beta-catenin binding inhibitors than EpCAM-negative HCC in vitro. Taken together, our data indicate that EpCAM is a Wnt-beta-catenin signaling target gene and may be used to facilitate HCC prognosis by enabling effective stratification of patients with predicted pharmacologic responses to Wnt-beta-catenin signaling antagonists.}, address = {Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-4255, USA.}, author = {Yamashita, T. and Budhu, A. and Forgues, M. and Wang, X. W. }, citeulike-article-id = {2955054}, doi = {10.1158/0008-5472.CAN-07-0908}, issn = {1538-7445}, journal = {Cancer research}, keywords = {catenin, hcc, liver, stem-cell, wnt}, month = {November}, number = {22}, pages = {10831--10839}, posted-at = {2008-07-03 06:51:22}, priority = {2}, title = {Activation of hepatic stem cell marker EpCAM by Wnt-beta-catenin signaling in hepatocellular carcinoma.}, url = {http://dx.doi.org/10.1158/0008-5472.CAN-07-0908}, volume = {67}, year = {2007} }

TY - JOUR ID - citeulike:2955054 L3 - citeulike-article-id:2955054 TI - Activation of hepatic stem cell marker EpCAM by Wnt-beta-catenin signaling in hepatocellular carcinoma. JF - Cancer research VL - 67 IS - 22 SP - 10831 EP - 10839 AD - Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892-4255, USA. SN - 1538-7445 N2 - The heterogeneous nature of hepatocellular carcinoma (HCC) and the lack of appropriate biomarkers have hampered patient prognosis and treatment stratification. Using a gene expression profiling approach, we recently identified a novel prognostic HCC subtype that resembles hepatic progenitor cells with the activation of stem cell markers and Wnt-beta-catenin signaling, based on EpCAM (epithelial cell adhesion molecule, a hepatic stem cell marker) expression. In this study, we investigated whether the activation of the Wnt-beta-catenin pathway regulates EpCAM expression. We found that nuclear accumulation of beta-catenin induced, whereas the degradation of beta-catenin or inhibition of Tcf/beta-catenin complex formation reduced EpCAM gene expression in cultured normal human hepatocytes and HCC cell lines. We identified two Tcf binding elements in the EpCAM promoter that specifically bound to Tcf-4 in an electrophoretic mobility shift assay. EpCAM promoter luciferase activity was down-regulated by the degradation of beta-catenin or inhibition of Tcf/beta-catenin complex formation. Furthermore, we found that EpCAM-positive HCC is much more sensitive to Tcf/beta-catenin binding inhibitors than EpCAM-negative HCC in vitro. Taken together, our data indicate that EpCAM is a Wnt-beta-catenin signaling target gene and may be used to facilitate HCC prognosis by enabling effective stratification of patients with predicted pharmacologic responses to Wnt-beta-catenin signaling antagonists. KW - catenin KW - hcc KW - liver KW - stem-cell KW - wnt AU - Yamashita, T AU - Budhu, A AU - Forgues, M AU - Wang, XW PY - 2007/11/15/ UR - http://dx.doi.org/10.1158/0008-5472.CAN-07-0908 ER -