The role of steroid receptor coactivator (SRC) in the development of prostate cancer

雄激素受体（Androgen receptor， AR）是一种核受体，它调节正常前列腺和前列腺癌的发展等重要生物学事件。一旦AR与其同源激素结合，它就会招募一组称为共激活因子的不同蛋白质来调节目标基因的表达。类固醇受体共激活因子（SRC）是核受体共激活因子p160家族的成员，由SRC-1、SRC-2和SRC-3组成。先前的研究表明，SRC-3在一些人类癌症中经常被扩增或过度表达。然而，src -3介导的生长调节机制尚不清楚。在这项研究中，我们发现SRC-3的过表达刺激细胞生长，增加前列腺癌细胞的细胞大小。我们分别用免疫组化和Western分析法检测了SRC-1、SRC-2和SRC-3在70例前列腺癌患者和人前列腺癌细胞中的表达水平。研究发现，47%的人前列腺癌样本（N=70）在肿瘤区域过表达SRC-3，而在邻近正常区域不表达SRC-3。总的来说，SRC-3的过表达与患者复发、激素依赖等特征相关。此外，我们建立了稳定的过表达SRC-3的LNCaP和PC3细胞系。我们利用这些细胞系研究SRC-3过表达对前列腺癌细胞生长的影响。SRC-3过表达的稳定细胞系细胞生长明显增加。SRC-3的过表达调节了AKT信号通路，导致AKT/mTOR信号通路激活，同时细胞大小增大。相反，通过小干扰RNA （small interfering RNA, siRNA）下调细胞中SRC-3的表达会降低细胞生长，导致细胞尺寸变小。这些发现提示SRC-3的表达水平可能是前列腺癌肿瘤形成、转移和雄激素依赖的另一个生物标志物。

Androgen receptor (AR) is a nuclear receptor, which regulates important biological events such as development of the normal prostate gland and prostate cancers. Once AR is bound to its cognate hormone, it recruits a diverse group of proteins called coactivators to regulate expression of target genes. Steroid Receptor Coactivator (SRC) is a member of the p160 family of nuclear receptor coactivators, which consists of SRC-1,SRC-2 and SRC-3. Previous studies indicate that SRC-3 is often amplified or overexpressed in some human cancers. However, the mechanisms of SRC-3-mediated growth regulation remain unclear. In this study, we show that overexpression of SRC-3 stimulates cell growth to increase cell size in prostate cancer cell.We examined the expression level of SRC-1,SRC-2 and SRC-3 in 70 prostate cancer patients' samples and human prostate cancer cell lines by immunohistochemistry and Western analysis, respectively. It was found that 47% of human prostate cancer samples (N=70) overexpresses SRC-3 in the tumor area but not in the adjacent normal area. In general, the over-expression of SRC-3 correlated with patients' characteristics such as recurrence and hormone dependency. In addition, we established stable LNCaP and PC3 cell lines over-expressing SRC-3. These cell lines were used to investigate the effect of SRC-3 over-expression in prostate cancer cell growth. It was observed a significant increase in cell growth of stable cell lines with overexpression of SRC-3. And overexpression of SRC-3 modulated the AKT signaling pathway, which results in the activation of AKT/mTOR signaling concomitant with an increase in cell size. In contrast, down-regulation of SRC-3 expression in cells by small interfering RNA (siRNA) decreases cell growth, leading to a smaller cell size.These findings suggest that the expression levels of SRC-3 may be an additional biomarker for the tumor formation, metastasis and androgen dependency in prostate cancers.