Abstract
The poor prognosis for hepatocellular carcinoma (HCC) is associated with a high rate of its intrahepatic recurrence. Therefore, the development of a chemopreventive agent that can decrease or delay the incidence of recurrence will improve the clinical outcome of HCC patients. A malfunction of the retinoid X receptor-α (RXRα) due to phosphorylation by the Ras-MAPK signaling pathway is profoundly involved in liver carcinogenesis and thus may be a promising target for HCC chemoprevention. Acyclic retinoid (ACR), which inhibits Ras-MAPK activation and RXRα phosphorylation, successfully improves the survival of HCC patients by preventing the recurrence of the tumor and the formation of secondary tumors. The fundamental concept of HCC chemoprevention by ACR is "clonal deletion and inhibition" therapy, which is defined as the removal and inhibition of latent malignant clones from the liver before they expand into clinically detectable HCC. "Combination chemoprevention" using ACR as the key drug has a great potential to become an effective strategy for the prevention of liver carcinogenesis because of its synergism. ACR also inhibits obesity-related liver tumorigenesis in the rodent model, indicating that this agent may prevent the development of HCC in obese people who are at an increased risk to HCC. In summary, both basic and clinical researches strongly suggest that ACR plays a critical role in preventing the development of HCC.
