核受體是一類主要在核內(nèi)工作的蛋白質(zhì),，但在疾病如癌癥發(fā)生發(fā)展過程中，這類蛋白會通過某種機(jī)制穿梭轉(zhuǎn)位于細(xì)胞質(zhì),，執(zhí)行與其核內(nèi)轉(zhuǎn)錄調(diào)控作用不同的生物學(xué)功能,，來自廈門大學(xué)生物醫(yī)學(xué)院的曾錦章教授和張曉坤教授關(guān)于核受體RARg異常轉(zhuǎn)位激活肝癌細(xì)胞生長通道研究取得新進(jìn)展。
作為一類依賴于特異性配體激活的多功能蛋白質(zhì),，核受體在核內(nèi)通過作用于靶基因的啟動子或增強(qiáng)子應(yīng)答元件,，調(diào)控基因轉(zhuǎn)錄進(jìn)而控制細(xì)胞的生命活動,，這是傳統(tǒng)意義上的核受體功能,。近10年來，核受體的另一種可以在細(xì)胞質(zhì)中快速調(diào)控細(xì)胞應(yīng)激反應(yīng)的新機(jī)制在國際上引起廣泛的注意,。該文章報(bào)道,，在肝癌中，大量表達(dá)的RARg位于癌細(xì)胞的胞漿內(nèi),，通過與PI3K的調(diào)節(jié)亞基p85作用,，激活PI3K/Akt和NF-kB信號轉(zhuǎn)導(dǎo)通路，誘導(dǎo)甲胎蛋白AFP的轉(zhuǎn)錄與表達(dá),，有趣的是,，RARg靶點(diǎn)可以被肝癌的致病因子黃曲霉毒素以及環(huán)磷酰胺抗癌藥分別上調(diào)和下調(diào)，并因而影響該通路中AFP的表達(dá),。AFP表達(dá)水平的變化可敏感地反應(yīng)肝癌細(xì)胞增殖活躍程度,，該研究表明，肝癌中過表達(dá)的RARg及其依賴的生長信號轉(zhuǎn)導(dǎo)通路是一個潛在的治療靶位,。
該文章是繼廈門大學(xué)生物醫(yī)學(xué)院癌癥研究中心于2009年在JBC雜志（與美國Burnham醫(yī)學(xué)研究所合作）發(fā)表關(guān)于RARg在細(xì)胞核內(nèi)外穿梭調(diào)控機(jī)制文章的又一篇力作,。(生物谷Bioon.com)
生物谷推薦原文出處：
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
