MiR-573 inhibits prostate cancer metastasis by regulating epithelial-mesenchymal transition.
MiR-573 inhibits prostate cancer metastasis by regulating epithelial-mesenchymal transition.
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miR-573通过调节上皮间质转化抑制前列腺癌转移
DOI：
10.18632/oncotarget.5427
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发表时间：
2015-11-03
期刊：
影响因子：
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通讯作者：
Han B
中科院分区：
文献类型：
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作者：
Wang L;Song G;Tan W;Qi M;Zhang L;Chan J;Yu J;Han J;Han B
前列腺癌（PCa）中的细胞级联反应是一个复杂的过程，在多个水平上受到调节。最近的证据表明，微小RNA（miRNA）参与PCa转移，并作为治疗靶点具有很大的希望。在这项研究中，我们发现miR-573在转移组织中的表达显著低于匹配的原发性PCa。其下调与PCa患者的高Gleason评分和癌症相关死亡率相关（P = 0.041，Kaplan-Meier分析）。通过功能获得和丧失实验，我们证明了miR-573在体外抑制PCa细胞迁移、侵袭和TGF-β1诱导的上皮-间充质转化（EMT）以及在体内抑制肺转移。从机制上讲，miR 573直接靶向成纤维细胞生长因子受体1（FGFR 1）基因。FGFR 1的敲低表型复制了miR-573表达对PCa细胞侵袭的作用，而FGFR 1的过表达部分减弱了miR-573的功能。因此，miR-573响应成纤维细胞生长因子2（FGF 2）调节FGFR 1下游信号传导的激活。重要的是，我们发现GATA 3直接增加miR-573表达，从而以miR-573依赖性方式下调FGFR 1表达、EMT和PCa细胞的侵袭，支持GATA 3、miR-573和FGFR 1参与控制PCa转移期间的EMT过程。总之，我们的研究结果证明了miR-573调节EMT和PCa细胞转移的新机制，并建议miR-573作为PCa管理的潜在生物标志物和/或治疗靶点。
The metastastic cascade is a complex process that is regulated at multiple levels in prostate cancer (PCa). Recent evidence suggests that microRNAs (miRNAs) are involved in PCa metastasis and hold great promise as therapeutic targets. In this study, we found that miR-573 expression is significantly lower in metastatic tissues than matched primary PCa. Its downregulation is correlated with high Gleason score and cancer-related mortality of PCa patients (P = 0.041, Kaplan-Meier analysis). Through gain- and loss-of function experiments, we demonstrated that miR-573 inhibits PCa cell migration, invasion and TGF-β1-induced epithelial-mesenchymal transition (EMT) in vitro and lung metastasis in vivo. Mechanistically, miR573 directly targets the fibroblast growth factor receptor 1 (FGFR1) gene. Knockdown of FGFR1 phenocopies the effects of miR-573 expression on PCa cell invasion, whereas overexpression of FGFR1 partially attenuates the functions of miR-573. Consequently, miR-573 modulates the activation of FGFR1-downstream signaling in response to fibroblast growth factor 2 (FGF2). Importantly, we showed that GATA3 directly increases miR-573 expression, and thus down-regulates FGFR1 expression, EMT and invasion of PCa cells in a miR-573-dependent manner, supporting the involvement of GATA3, miR-573 and FGFR1 in controlling the EMT process during PCa metastasis. Altogether, our findings demonstrate a novel mechanism by which miR-573 modulates EMT and metastasis of PCa cells, and suggest miR-573 as a potential biomarker and/or therapeutic target for PCa management.