核受体是一类主要在核内工作的蛋白质，但在疾病如癌症发生发展过程中，这类蛋白会通过某种机制穿梭转位于细胞质，执行与其核内转录调控作用不同的生物学功能，来自厦门大学生物医学院的曾锦章教授和张晓坤教授关于核受体RARg异常转位激活肝癌细胞生长通道研究取得新进展。
作为一类依赖于特异性配体激活的多功能蛋白质，核受体在核内通过作用于靶基因的启动子或增强子应答元件，调控基因转录进而控制细胞的生命活动，这是传统意义上的核受体功能。近10年来，核受体的另一种可以在细胞质中快速调控细胞应激反应的新机制在国际上引起广泛的注意。该文章报道，在肝癌中，大量表达的RARg位于癌细胞的胞浆内，通过与PI3K的调节亚基p85作用，激活PI3K/Akt和NF-kB信号转导通路，诱导甲胎蛋白AFP的转录与表达，有趣的是，RARg靶点可以被肝癌的致病因子黄曲霉毒素以及环磷酰胺抗癌药分别上调和下调，并因而影响该通路中AFP的表达。AFP表达水平的变化可敏感地反应肝癌细胞增殖活跃程度，该研究表明，肝癌中过表达的RARg及其依赖的生长信号转导通路是一个潜在的治疗靶位。
该文章是继厦门大学生物医学院癌症研究中心于2009年在JBC杂志（与美国Burnham医学研究所合作）发表关于RARg在细胞核内外穿梭调控机制文章的又一篇力作。(生物谷Bioon.com)
生物谷推荐原文出处：
Cancer Research doi: 10.1158/0008-5472.CAN-09-2968
Oncogenic Potential of Retinoic Acid Receptor- in Hepatocellular Carcinoma
Ting-Dong Yan1, Hua Wu1, Hai-Ping Zhang2, Na Lu1, Ping Ye3, Feng-Hai Yu3, Hu Zhou4, Wen-Gang Li2, Xihua Cao4, Ya-Yu Lin1, Jia-You He1, Wei-Wei Gao1, Yi Zhao1, Lei Xie1, Jie-bo Chen4, Xiao-kun Zhang1,4 and Jin-Zhang Zeng1
Retinoic acid receptors (RAR; , β, and ), 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 were significantly elevated in tumor tissues from a majority of human hepatocellular carcinoma (HCC) and in HCC cell lines. Overexpression of RAR promoted colony formation by HCC cells in vitro and the growth of HCC xenografts in animals. In HepG2 cells, transfection of RAR enhanced, whereas downregulation of RAR expression by siRNA approach impaired, the effect of RA on inducing the expression of -fetoprotein, a protein marker of hepatocarcinogenesis. In studying the possible mechanism by which overexpression of RAR contributed to liver cancer cell growth and transformation, we observed that RAR resided mainly in the cytoplasm of HCC cells, interacting with the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K). The interaction between RAR and p85resulted in activation of Akt and NF-B, critical regulators of the growth and survival of cancer cells. Together, our results show that overexpression of RAR plays a role in the growth of HCC cells through nongenomic activation of the PI3K/Akt and NF-B signaling pathways.
1 Institute for Biomedical Research, Xiamen University; 2 First Hospital of Xiamen, Xiamen, China; 3 Eastern Hepatobiliary Surgery Hospital, Shanghai, China; and 4 Burnham Institute for Medical Research, La Jolla, California
