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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/β-catenin signaling occurs preferentially within the oval cell population, and forced expression of constitutively active β-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/β-catenin signaling. These OV6⁺ HCC cells possess a greater ability to form tumor in vivo and show a substantial resistance to standard chemotherapy …