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|Title:||A ZEB1-miR-375-YAP1 pathway regulates epithelial plasticity in prostate cancer|
|Citation:||Oncogene, 2017; 36(1):24-34|
|Publisher:||Nature Publishing Group|
|LA Selth, R Das, SL Townley, I Coutinho, AR Hanson, MM Centenera, N Stylianou, K Sweeney, C Soekmadji, L Jovanovic, CC Nelson, A Zoubeidi, LM Butler, GJ Goodall, BG Hollier, PA Gregory, and WD Tilley|
|Abstract:||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.|
|Keywords:||Epithelium; Cell Line, Tumor; Animals; Humans; Prostatic Neoplasms; Adaptor Proteins, Signal Transducing; Phosphoproteins; Transcription Factors; MicroRNAs; 3' Untranslated Regions; Signal Transduction; Gene Expression; Gene Expression Regulation, Neoplastic; RNA Interference; Phenotype; Male; Proto-Oncogene Proteins c-met; Neoplastic Cells, Circulating; Epithelial-Mesenchymal Transition; Biomarkers; Zinc Finger E-box-Binding Homeobox 1|
|Rights:||© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved|
|Appears in Collections:||Medical Education Unit publications|
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