Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells.

Abstract

Adult hepatic progenitor (oval) cells are facultative stem cells in liver, which participate in a range of human liver diseases, including hepatocellular carcinoma (HCC). However, the molecular pathways regulating the expansion and differentiation of these cells are poorly understood. We show that active Wnt/beta-catenin signaling occurs preferentially within the oval cell population, and forced expression of constitutively active beta-catenin mutant promotes expansion of the oval cell population in the regenerated liver. More importantly, we identify a subpopulation of less differentiated progenitor-like cells in HCC cell lines and primary HCC tissues, which are defined by expression of the hepatic progenitor marker OV6 and endowed with endogenously active Wnt/beta-catenin signaling. These OV6(+) HCC cells possess a greater ability to form tumor in vivo and show a substantial resistance to standard chemotherapy compared with OV6(-) tumor cells. The fraction of tumor cells expressing OV6 is enriched after Wnt pathway activation, whereas inhibition of beta-catenin signaling leads to a decrease in the proportion of OV6(+) cells. In addition, the chemoresistance of OV6(+) HCC progenitor-like cells can be reversed by lentivirus-delivered stable expression of microRNA targeting beta-catenin. These results highlight the importance of the Wnt/beta-catenin pathway in activation and expansion of oval cells in normal rodent models and human HCCs. OV6(+) tumor cells may represent the cellular population that confers HCC chemoresistance, and therapies targeted to the Wnt/beta-catenin signaling may provide a specific method to disrupt this resistance mechanism to improve overall tumor control with chemotherapy.

DOI: 10.1158/0008-5472.CAN-07-6691

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@article{Yang2008WntbetacateninSC, title={Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells.}, author={Wen Yang and He-xin Yan and Lei Chen and Qiong Liu and Ya-qin He and Le-xing Yu and Shu-hui Zhang and Dan-dan Huang and Liang Tang and Xiao-ni Kong and Chao Chen and Shu-qin Liu and Meng-chao Wu and Hong-Yang Wang}, journal={Cancer research}, year={2008}, volume={68 11}, pages={4287-95} }