期刊
ONCOGENE
卷 36, 期 1, 页码 24-34出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2016.185
关键词
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资金
- Young Investigator Awards from the Prostate Cancer Foundation [14]
- Prostate Cancer Foundation of Australia (PCFA)/Movember [YI 0810, YI 0412]
- PCFA/Movember/Cancer Australia [1012337, 1043482]
- National Health and Medical Research Council [1083961]
- Cancer Council of South Australia
- Queensland government Smart Futures Fund Fellowship
- Movember Foundation
- Prostate Cancer Foundation of Australia through Movember Revolutionary Team Awards
- National Health and Medical Research Council of Australia [1083961] Funding Source: NHMRC
- National Breast Cancer Foundation [CG-10-04] Funding Source: researchfish
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.
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