Wnt/β-Catenin Signaling Contributes To Activation Of Normal And Tumorigenic Liver Progenitor Cells

PartⅠWnt/β-Catenin Signaling Mediates Progenitor Cells Activation in RodentsAdult hepatic progenitor cells (oval cells) are facultative stem cells in the liver that are activated during regeneration only during inhibition of innate hepatocyte proliferation. On the basis of its involvement in liver development, regeneration, and cancer, we investigated the role of the Wnt/β-catenin pathway in progenitor cell activation, which was initiated in rats with 2-acetylaminofluorine and two-third partial hepatectomy (PH) and in mice with treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine. First, we showed thatβ-catenin is highly expressed and mainly localized to the proliferating oval cells in both rat and mouse models, indicating the role of canonical Wnt/β-catenin pathway during the regenerative response. Furthermore, constitutive activation of Wnt/β-catenin signaling stimulated progenitor cell proliferation in vitro and caused a substantial clonal expansion of the transplanted rat oval cells in vivo, indicating that the activated Wnt/β-catenin signaling is required for progenitor cell expansion. Finally, the hyperplastic phenotype was consistently observed in the livers of DDC-fed mice that transiently overexpressed the constitutively activeβ-catenin. These results indicated that Wnt/β-catenin signaling occurs preferentially within the oval cell population, and forced expression of constitutively activeβ-catenin mutant promotes expansion of the progenitor cell population in the regenerated liver. PartⅡWnt/β-Catenin Signaling Contributes to Activation of Tumorigenic Liver Progenitor CellsTransformed hematopoietic stem/progenitor cells with an enhanced or acquired self-renewal capability function as leukemic stem cells. In a variety of solid cancers, stem/progenitor cells could be also targets of carcinogenesis. In the present study, 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/β-catenin signaling. These OV6-positive HCC cells possess a greater ability to form tumor in vivo and show a substantial resistance to standard chemotherapy as compared to OV6-negative tumor cells. The fraction of tumor cells expressing OV6 is enriched after Wnt pathway activation whereas inhibition ofβ-catenin signaling leads to a decrease in the proportion of OV6-positive cells. In addition, the chemoresistance of OV6-positive HCC progenitor-like cells can be reversed by lentivirus-delivered stable expression of microRNA targetingβ-catenin. These results highlight the importance of the Wnt/β-catenin pathway in activation and expansion of oval cells in human HCCs. OV6-positive tumor cells may represent the cellular population that confers HCC chemoresistance and therapies targeted to the Wnt/β-catenin signaling may provide a specific method to disrupt this resistance mechanism to improve overall tumor control with chemotherapy.