Medical Learning and Teaching Unit

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Browsing Medical Learning and Teaching Unit by Author "Centenera, M."

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    A ZEB1-miR-375-YAP1 pathway regulates epithelial plasticity in prostate cancer
    (Nature Publishing Group, 2017) Selth, L.; Das, R.; Townley, S.; Coutinho, I.; Hanson, A.; Centenera, M.; Stylianou, N.; Sweeney, K.; Soekmadji, C.; Jovanovic, L.; Nelson, C.; Zoubeidi, A.; Butler, L.; Goodall, G.; Hollier, B.; Gregory, P.; Tilley, W.
    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.