Genomic analysis of human hepatocellular carcinoma (HCC) is potentially confounded by the differentiation state of the hepatic cell-of-origin. Here we integrated genomic analysis of mouse HCC (with defined cell-of-origin) along with normal development. We found a major shift in expression of Wnt and RXR-alpha pathway genes (up and down, respectively) coincident with the transition from hepatoblasts to hepatocytes. A combined Wnt and RXR-alpha gene signature categorized HCCs into two subtypes (high Wnt, low RXR-alpha and low Wnt, high RXR-alpha), which matched cell-of-origin in mouse models and the differentiation state of human HCC. Suppression of RXR-alpha levels in hepatocytes increased Wnt signaling and enhanced tumorigenicity, whereas ligand activation of RXR-alpha achieved the opposite. These results corroborate that there are two main HCC subtypes that correspond to the degree of hepatocyte differentation and that RXR-alpha, in part via Wnt signaling, plays a key functional role in the hepatocyte-like subtype and potentially could serve as a selective therapeutic target.
School of Medicine