A ZEB1-miR-375-YAP1 pathway regulates epithelial plasticity in prostate cancer

被引：96

作者：

Selth, L. A. ^{[1
,2
,3
]}

Das, R. ^{[1
,2
,3
]}

Townley, S. L. ^{[1
,2
,3
]}

Coutinho, I. ^{[1
,2
,3
]}

Hanson, A. R. ^{[1
,2
,3
]}

Centenera, M. M. ^{[2
,3
,4
]}

Stylianou, N. ^{[5
]}

Sweeney, K. ^{[5
]}

Soekmadji, C. ^{[5
]}

Jovanovic, L. ^{[5
]}

Nelson, C. C. ^{[5
]}

Zoubeidi, A. ^{[6
]}

Butler, L. M. ^{[2
,3
,4
]}

Goodall, G. J. ^{[3
,7
,8
,9
]}

HoIlier, B. G. ^{[5
]}

Gregory, P. A. ^{[3
,7
]}

Tilley, W. D. ^{[1
,2
,3
]}

机构：

[1] Univ Adelaide, Sch Med, Dame Roma Mitchell Canc Res Labs, Level 4,Hanson Inst Bldg,DX 650 801, Adelaide, SA 5005, Australia

[2] Univ Adelaide, Freemasons Fdn, Ctr Mens Hlth, Discipline Med, Adelaide, SA, Australia

[3] Univ Adelaide, Discipline Med, Adelaide, SA, Australia

[4] South Australian Hlth & Med Res Inst, Canc Theme, Adelaide, SA, Australia

[5] Queensland Univ Technol, Princess Alexandra Hosp, Translat Res Inst,Inst Hlth & Biomed Innovat, Australian Prostate Canc Res Ctr Queensland, Brisbane, Qld, Australia

[6] Univ British Columbia, Vancouver Prostate Ctr, Vancouver, BC, Canada

[7] SA Pathol, Ctr Canc Biol, Adelaide, SA, Australia

[8] Univ South Australia, Adelaide, SA, Australia

[9] Univ Adelaide, Sch Mol & Biomed Sci, Adelaide, SA, Australia

来源：

ONCOGENE | 2017年 / 36卷 / 01期

基金：

英国医学研究理事会;

关键词：

MICRORNA EXPRESSION PROFILES; CIRCULATING TUMOR-CELLS; MESENCHYMAL TRANSITION; ANDROGEN RECEPTOR; METASTATIC COLONIZATION; MIR-200; FAMILY; BREAST-CANCER; MESSENGER-RNA; PROGRESSION; REPRESSION;

D O I：

10.1038/onc.2016.185

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：24 / 34

页数：11

共 55 条

[1] Genomic profiling of MicroRNA and messenger RNA reveals deregulated MicroRNA expression in prostate cancer [J].