The identification of the specific molecular targets, which underlie liver
carcinogenesis is essential for the establishment of an effective strategy for the prevention and/or treatment of
hepatocellular carcinomas (HCCs). We previously found that a malfunction of RXRalpha due to its aberrant phosphorylation was associated with the development of HCCs. However, it has remained unclear whether the abnormalities in the expression of RXRalpha or the other
retinoid receptors play a role in the early stage of liver
carcinogenesis. The present study was designed to determine whether alterations in the expression of RXRalpha and the other
retinoid receptors RARalpha and RARbeta are involved in hepatocarcinogenesis using a
3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB)-induced rat liver
carcinogenesis model. We found that immunohistochemical expression of RXRalpha was decreased in liver cell
tumors (HCCs and
adenoma) and
glutathione S-transferase placental form (GST-P)-positive foci, which is a precancerous lesion of HCC, when compared with the non-cancerous tissues. Western blot and RT-PCR analyses revealed a progressive decrease in the expression levels of RXRalpha, RARalpha, and RARbeta
proteins and their mRNAs in 3'-MeDAB-induced HCCs and their surrounding tissues, when compared with the normal liver tissues from the control group. Moreover, the expression level of
beta-catenin, the heterodimeric partner for both RXRalpha and RARalpha, was immunohistochemically observed in the cytoplasm and, in some cases, in the nucleus of HCC cells. The nuclear expression of
cyclin D1, the downstream target molecule of
beta-catenin, was also increased in HCC cells when compared with their adjacent normal appearing tissues. Our findings suggest that loss of
retinoid receptors, especially RXRalpha, plays a critical role in the chemically-induced rat liver
carcinogenesis and this might be associated with the activation of
beta-catenin-related signaling pathway.