Oncogenic Potential of Retinoic Acid Receptor-γ in Hepatocellular Carcinoma

Retinoic acid receptors (RAR; alpha, beta, and gamma), members of the nuclear receptor superfamily, mediate the pleiotropic effects of the vitamin A metabolite retinoic acid (RA) and derivatives (retinoids) in normal and cancer cells. Abnormal expression and function of RARs are often involved in the growth and development of cancer. However, the underlying molecular mechanisms remain largely elusive. Here, we report that levels of RAR gamma were significantly elevated in tumor tissues from a majority of human hepatocellular carcinoma (HCC) and in HCC cell lines. Overexpression of RAR gamma promoted colony formation by HCC cells in vitro and the growth of HCC xenografts in animals. In HepG2 cells, transfection of RAR gamma enhanced, whereas downregulation of RAR gamma expression by siRNA approach impaired, the effect of RA on inducing the expression of alpha-fetoprotein, a protein marker of hepatocarcinogenesis. In studying the possible mechanism by which overexpression of RAR gamma contributed to liver cancer cell growth and transformation, we observed that RAR gamma resided mainly in the cytoplasm of HCC cells, interacting with the p85 alpha regulatory subunit of phosphatidylinositol 3-kinase (PI3K). The interaction between RAR gamma and p85 alpha resulted in activation of Akt and NF-kappa B, critical regulators of the growth and survival of cancer cells. Together, our results show that overexpression of RAR gamma plays a role in the growth of HCC cells through nongenomic activation of the PI3K/Akt and NF-kappa B signaling pathways. Cancer Res; 70(6); 2285-95. (C) 2010 AACR.