Expression of retinoic acid receptor genes in developing rat livers and hepatoma cells

The expression of retinoic acid receptor alpha, beta, and gamma mRNA was examined in developing rat livers and rat hepatoma-derived cell lines H-4-II-E, McA-RH 7777, and 8994 that represent different hepatocyte phenotypes. Northern blot hybridization demonstrated that all three receptor mRNAs were expressed in the fetal livers of different gestational ages, and the levels of expression increased significantly 3 to 4 weeks after birth. In the hepatoma cell lines, the expression pattern of retinoic acid receptor alpha and gamma mRNA did not correlate with the phenotype. In contrast, retinoic acid receptor beta mRNA was only detected in the adult phenotypic H-4-II-E cells but not in McA-RH 7777 and 8994 cells, which represent embryonic and fetal hepatocyte phenotypes, respectively. The levels of retinoic acid receptor beta mRNA in hepatoma cell lines were lower than adult rat liver. These data suggest that the increased expression of retinoic acid receptor beta gene is associated with differentiation or maturation of rat hepatocytes. The effect of retinoic acid on retinoic acid receptor gene expression was also studied in hepatoma cells. Retinoic acid did not regulate retinoic acid receptor gene expression in McA-RH 7777 and 8994 cells, and the retinoic acid receptor beta gene remained inactivated in these cells. However, Southern blot hybridization indicated that the gross structure of retinoic acid receptor beta gene was not altered during malignant transformation. In H-4-II-E cells, retinoic acid increased the expression of retinoic acid receptor beta and gamma gene. Because of the similarity between H-4-II-E cells and normal adult hepatocytes, this type of autoregulation may be a mechanism by which retinoic acid regulates its own effect in vivo.