REGULATION OF HEPATOCARCINOGENESIS BY ACYCLIC RETINOID

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Retinoid inhibit the tumor promotion phase of mutistep carcinogenesis. We have conducted investigations of chemoprevention of hepatocellular carcinoma by retionoids and confirmed the clinical effects of acyclic retionid, a synthetic retinoid analog, on second primary hepatocarcinogenesis. Interferons ( IFNs )-α and - β also induce apoptosis of hepatocellular carcinoma ( HCC ) cells and are used clinically in the prevention of HCC. Acyclic retinoid enhanced anti-tumor effects of not only IFN-β but also IFN-α, however, natural retinoic acid ( all-trans and 9-cis retinoic acid ) failed to exert such effect. This combination effect was likely due to enhanced apoptosis Mnduction as characterized by DNA fragmentation and chromatin condensation. Pretreatment of the HCC cells with acyclic retinoid followed by IFN-β, but not the converse, induced such cytotoxic effect. Acyclic retinoid increased the expression of type 1 IFN receptor ( IFNR ) and inclusion with anti-type 1 IFNR antibody abolished the synergistic growth suppression by the combination. Moreover, the retinoid up-regulated the expression and DNA-binding activity of STAT1, an intracellular signal transducing molecule of IFNR. Thus, acyclic retinoid seemed to enhance the sensitivity of HCC cells to IFN-β and thereby promoted the cancer cell death. These results suggest a future clinical use of the combination of acyclic retinoid and IFN-β in the biochemoprevention of HCC. We evaluate these results as very important to establish cancer chemoprevention with retionids and to develop novel cancer chemopreventive agents.