Institute for Biomedical Research, Xiamen University; First Hospital of Xiamen, Xiamen, China.
Cancer Res. 2010 Mar 15;70(6):2285-95. doi: 10.1158/0008-5472.CAN-09-2968. Epub 2010 Mar 2.
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.
维甲酸受体（RAR；α、β 和 γ）属于核受体超家族成员，介导维生素 A 代谢产物维甲酸（RA）及其衍生物（类视黄醇）在正常细胞和癌细胞中的多效性作用。RAR 的异常表达和功能常涉及癌症的生长和发展。然而，其潜在的分子机制在很大程度上仍未被揭示。在这里，我们报告 RARγ 在大多数人肝癌（HCC）的肿瘤组织和 HCC 细胞系中均显著上调。RARγ 的过表达促进 HCC 细胞在体外的集落形成，并促进 HCC 异种移植物在动物体内的生长。在 HepG2 细胞中，RARγ 的转染增强了 RA 诱导甲胎蛋白（一种肝癌发生的蛋白标志物）表达的作用，而通过 siRNA 方法下调 RARγ 表达则削弱了该作用。在研究 RARγ 的过表达如何促进肝癌细胞生长和转化的可能机制时，我们观察到 RARγ 主要位于 HCC 细胞的细胞质中，与磷酸肌醇 3-激酶（PI3K）的 p85α 调节亚基相互作用。RARγ 与 p85α 的相互作用导致 Akt 和 NF-κB 的激活，这是癌细胞生长和存活的关键调节因子。总之，我们的结果表明，RARγ 的过表达通过非基因组激活 PI3K/Akt 和 NF-κB 信号通路在 HCC 细胞的生长中发挥作用。
