The androgen receptor negatively regulates the expression of c-Met: Implications for a novel mechanism of prostate cancer progression
The androgen receptor negatively regulates the expression of c-Met: Implications for a novel mechanism of prostate cancer progression
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DOI：
10.1158/0008-5472.can-06-3552
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发表时间：
2007-02-01
期刊：
影响因子：
11.2
通讯作者：
Sun, Zijie
中科院分区：
文献类型：
--
作者：
Verras, Meletios;Lee, Jane;Sun, Zijie
前列腺癌细胞从雄激素敏感状态发展到雄激素不敏感状态的确切分子机制仍然很大程度上仍不清楚。肝细胞生长因子/散射因子(HGF/SF)在调节细胞生长、运动、形态发生和血管生成等方面发挥重要作用。在包括前列腺癌在内的多种人类恶性肿瘤中，HGF/SF及其受体c-Met的异常表达往往与预后不良有关。在这里，我们调查了前列腺癌细胞中雄激素信号和c-Met表达之间的潜在联系。首先，我们发现雄激素受体(AR)以配体依赖的方式抑制c-Met的表达。利用不同的c-Met启动子/报告结构，我们发现SPL可以诱导前列腺癌c-Met的转录，AR可以抑制SPL诱导的c-Met转录。此外，电泳迁移率改变分析的数据表明，AR干扰了SPL与c-Met启动子内功能性SPL结合部位之间的相互作用。此外，我们还测试了AR对雄激素不敏感的前列腺癌细胞系CWR22Rv1 c-Met表达的影响。最后，在前列腺癌移植瘤中证实了雄激素信号对c-Met表达的抑制作用。上述数据表明，AR在转录调控中具有双重作用。虽然目前的雄激素消融治疗可以抑制AR激活的促生长基因的表达，但它也可能减弱AR对c-Met表达的抑制作用。因此，抑制HGF/c-Met途径激活的治疗策略与目前的雄激素治疗相结合可能是有益的。
The precise molecular mechanisms by which prostate cancer cells progress from androgen-sensitive to androgen-insensitive status still remain largely unclear. The hepatocyte growth factor/scatter factor (HGF/SF) plays a critical role in the regulation of cell growth, cell motility, morphogenesis, and angiogenesis. The aberrant expression of HGF/SF and its receptor, c-Met, often correlates with poor prognosis in a variety of human malignancies, including prostate cancer. Here, we investigate a potential link between androgen signaling and c-Met expression in prostate cancer cells. First, we showed that the androgen receptor (AR) represses the expression of c-Met in a ligand-dependent manner. Using different c-Met promoter/reporter constructs, we identified that Spl induces the transcription of c-Met and that AR can repress the Spl-induced transcription in prostate cancer cells. Moreover, the data from electrophoretic mobility shift assay showed that AR interferes with the interaction between Spl and the functional Spl binding site within the c-Met promoter. Furthermore, we tested the effect of AR on c-Met expression fit an androgen-insensitive prostate cancer cell line, CWR22Rv1. Finally, the repressive role of androgen signaling on c-Met expression was confirmed in prostate cancer xenografts. The above data indicate a dual role of AR in transcriptional regulation. Although the current androgen ablation therapy can repress the expression of growthpromoting genes that are activated by the AR, it may also attenuate the repressive role of AR on c-Met expression. Therefore, the therapeutic strategies to inhibit the activation of the HGF/c-Met pathway may be of benefit when combined with current androgen ablation treatment.