Strategy for the chemoprevention of hepatocellular carcinoma by targeting phosphorylated RXRa

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A malfunction of RXRα due to phosphorylation by activation of the Ras/MAPK and PI3K/Akt signaling pathways is profoundly associated with the development of HCC and thus may be a critical target for HCC chemoprevention. A phase II/III trial of acyclic retinoid (ACR), which targets phosphorylated RXRα, to test its effectiveness in preventing second primary HCC in hepatitis C virus-positive patients is currently underway in Japan as a large-scale randomized placebo-controlled trial. In the present study, the combination of ACR plus specific agent, which targets growth factor receptors, the Ras/MAPK and PI3K/Akt signaling pathways, inhibit the RXRα phosphorylation and it may therefore be a promising strategy to prevent the development of HCC. These findings suggest that the inhibition of RXRα phosphorylation and the restoration of its physiological function as a master regulator for nuclear receptors may be a potentially effective strategy for HCC chemoprevention and treatment.