A ZEB1-miR-375-YAP1 pathway regulates epithelial plasticity in prostate cancer
A ZEB1-miR-375-YAP1 pathway regulates epithelial plasticity in prostate cancer
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DOI：
10.1038/onc.2016.185
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发表时间：
2017-01-05
期刊：
影响因子：
8
通讯作者：
Tilley, W. D.
中科院分区：
文献类型：
--
作者：
Selth, L. A.;Das, R.;Tilley, W. D.
MicroRNA-375（miR-375）在前列腺肿瘤和患者血液的无细胞部分中经常升高，但其在前列腺癌发生和发展中的作用知之甚少。在这项研究中，我们证明了miR-375与临床样本中的上皮-间充质转化特征（EMT）呈负相关，并且可以在模型系统中驱动间充质-上皮转化（MET）。事实上，miR-375有效地抑制了多种前列腺癌细胞系的侵袭和迁移。发现转录因子YAP 1是前列腺癌中miR-375的直接靶点。敲除YAP 1表型复制miR-375过表达，而YAP 1过表达则挽救了miR-375介导的抗侵袭作用。此外，miR-375基因的转录被EMT转录因子ZEB 1直接抑制。对多个患者队列的分析为临床样本中的ZEB 1-miR-375-YAP 1调节回路提供了证据。尽管具有抗侵袭和抗EMT能力，但发现血浆miR-375与患有转移性疾病的男性中的循环肿瘤细胞相关。总的来说，这项研究为miR-375在前列腺癌中的功能提供了新的见解，并更广泛地确定了一种控制这种疾病中上皮可塑性和肿瘤细胞侵袭的新途径。
MicroRNA-375 (miR-375) is frequently elevated in prostate tumors and cell-free fractions of patient blood, but its role in genesis and progression of prostate cancer is poorly understood. In this study, we demonstrated that miR-375 is inversely correlated with epithelial-mesenchymal transition signatures (EMT) in clinical samples and can drive mesenchymal-epithelial transition (MET) in model systems. Indeed, miR-375 potently inhibited invasion and migration of multiple prostate cancer lines. The transcription factor YAP1 was found to be a direct target of miR-375 in prostate cancer. Knockdown of YAP1 phenocopied miR-375 overexpression, and overexpression of YAP1 rescued anti-invasive effects mediated by miR-375. Furthermore, transcription of the miR-375 gene was shown to be directly repressed by the EMT transcription factor, ZEB1. Analysis of multiple patient cohorts provided evidence for this ZEB1-miR-375-YAP1 regulatory circuit in clinical samples. Despite its anti -invasive and anti-EMT capacities, plasma miR-375 was found to be correlated with circulating tumor cells in men with metastatic disease. Collectively, this study provides new insight into the function of miR-375 in prostate cancer, and more broadly identifies a novel pathway controlling epithelial plasticity and tumor cell invasion in this disease.