Abstract
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 RARgamma were significantly elevated in tumor tissues from a majority of human hepatocellular carcinoma (HCC) and in HCC cell lines. Overexpression of RARgamma promoted colony formation by HCC cells in vitro and the growth of HCC xenografts in animals. In HepG2 cells, transfection of RARgamma enhanced, whereas downregulation of RARgamma 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 RARgamma contributed to liver cancer cell growth and transformation, we observed that RARgamma resided mainly in the cytoplasm of HCC cells, interacting with the p85alpha regulatory subunit of phosphatidylinositol 3-kinase (PI3K). The interaction between RARgamma and p85alpha resulted in activation of Akt and NF-kappaB, critical regulators of the growth and survival of cancer cells. Together, our results show that overexpression of RARgamma plays a role in the growth of HCC cells through nongenomic activation of the PI3K/Akt and NF-kappaB signaling pathways.
Highlights
Retinoic acid receptors (RAR) and retinoid X receptors (RXR) are members of the nuclear receptor superfamily, which mediate the pleiotropic effects of vitamin A metabolite retinoic acid (RA) and its natural and synthetic derivatives
We report that RARγ was overexpressed in hepatocellular carcinoma (HCC) tissues and cells and that overexpression of RARγ facilitated the growth of HCC cells through a RARγ/phosphatidylinositol 3-kinase (PI3K)/Akt/ NF-κB signaling axis
Our results showed that RARγ was overexpressed in a majority of HCC tissues (Fig. 1A) and in several HCC cell lines (Fig. 1C)
Summary
Retinoic acid receptors (RAR) and retinoid X receptors (RXR) are members of the nuclear receptor superfamily, which mediate the pleiotropic effects of vitamin A metabolite retinoic acid (RA) and its natural and synthetic derivatives (retinoids; refs. 1, 2). Retinoic acid receptors (RAR) and retinoid X receptors (RXR) are members of the nuclear receptor superfamily, which mediate the pleiotropic effects of vitamin A metabolite retinoic acid (RA) and its natural and synthetic derivatives Both RAR and RXR are encoded by three distinct genes, α, β, and γ, and they regulate a variety of important cellular processes in normal and cancer cells [1, 2]. The distinct spatial and temporal expression patterns of retinoid receptors during development and in adult tissues suggest that each of the subtypes has discrete functions [1, 2]. Altered expression and function of retinoid receptors are associated with the development of certain malignancies [3,4,5].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
