Reciprocal Interaction of Wnt and RXR-α Pathways in Hepatocyte Development and Hepatocellular Carcinoma

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.

Fatty acid oxidation and carnitine palmitoyltransferase I: emerging therapeutic targets in cancer

“…RXR has a vital role in the transcription of tumor suppressor genes which induce differentiation and suppress cancer growth. 78 , 79 As NR4 subfamily nuclear receptors (e.g., Nur77, NURR1) are ubiquitous heterodimerization partners of RXR in forming heterodimers, 80 current study also revealed that when the cancer cells are incubated with HX600, a selective RXR agonist for Nur77-RXR and NURR1-RXR, the expression of CPTIA is induced through Nur77 or NURR1-mediated mechanism in the teratocarcinoma cells or heptoma carcinoma HepG2 cells 81 ( Figure 3 ).…”

A genome-wide interactome of DNA-associated proteins in the human liver

“…3C; Supplemental Fig. S11), underscoring their importance in regulating liver-specific functions (Martinez-Jimenez et al 2010;DeLaForest et al 2011;Li et al 2015). Conversely, skin and cortex-specific genes exhibited a much lower enrichment for proximal DAP binding compared to liver-specific genes.…”

A genome-wide interactome of DNA-associated proteins in the human liver

“…We defined "liver-specific" genes as those with a mean RPKM, across all GTEx liver tissues, of at least two and at least five-fold higher than the mean RPKM in all other non-liver tissues. HNF4A and RXRA were the top TFs in terms of enrichment for binding near the TSSs of liver-specific genes ( Figure 3C, Supplemental Figure 9), underscoring their importance in regulating liverspecific functions (DeLaForest et al 2011;Martinez-Jimenez et al 2010;Li et al 2015).…”