Abstract
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-α pathway genes (up and down, respectively) coincident with the transition from hepatoblasts to hepatocytes. A combined Wnt and RXR-α gene signature categorized HCCs into two subtypes (high Wnt, low RXR-α and low Wnt, high RXR-α), which matched cell-of-origin in mouse models and the differentiation state of human HCC. Suppression of RXR-α levels in hepatocytes increased Wnt signaling and enhanced tumorigenicity, whereas ligand activation of RXR-α achieved the opposite. These results corroborate that there are two main HCC subtypes that correspond to the degree of hepatocyte differentation and that RXR-α, in part via Wnt signaling, plays a key functional role in the hepatocyte-like subtype and potentially could serve as a selective therapeutic target.
Highlights
Most hepatocellular carcinomas (HCCs) develop after years of chronic liver inflammation during which time small nodular lesions develop from clonal expansion of hepatocytes and/or hepatic progenitor cells [1]
There were relatively few broad copy number gains or losses in tumors arising from the transplantable mouse tumors, with broad losses involving chromosomes 4, 7, and 12 and broad gains involving chromosomes 2, 3, 5, 6, 8, 15, and 19 observed in 11% to 28% of the 18 transplantable mouse tumors, compared to the more frequent broad copy number alterations observed in human HCC (Fig. 1)
Despite years of genomic studies aimed at molecular classification of human HCC, there is still concern about lack of overlap between different studies[29]
Summary
Most hepatocellular carcinomas (HCCs) develop after years of chronic liver inflammation during which time small nodular lesions develop from clonal expansion of hepatocytes and/or hepatic progenitor cells [1]. The only clinical trials of agents that target this set of oncogenic drivers in HCC are ones involving inhibitors of Met, there is no biomarker guiding selection of patients in those trials [11]. Another possible avenue to matching HCC patients with specific treatments is through identification of molecular subtypes by transcriptional profiling. Tumors with TP53 mutations were associated with a proliferative class in one study but evenly distributed amongst all classes in a different study [12,13] Such inconsistencies add uncertainty to the preclinical development of therapies that target specific pathways and to advancement of predictive biomarkers
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