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Reciprocal Interaction of Wnt and RXR-[alpha] Pathways in Hepatocyte Development and Hepatocellular Carcinoma
Ist Teil von
PloS one, 2015-03, Vol.10 (3)
Ort / Verlag
Public Library of Science
Erscheinungsjahr
2015
Link zum Volltext
Quelle
EZB Free E-Journals
Beschreibungen/Notizen
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.