Serum levels of microRNA-194 (miR-194) have been reported to predict prostate cancer recurrence after surgery, but its functional contributions to this disease have not been studied. Herein, it is demonstrated that miR-194 is a driver of prostate cancer metastasis. Prostate tissue levels of miR-194 were associated with disease aggressiveness and poor outcome. Ectopic delivery of miR-194 stimulated migration, invasion and epithelial-mesenchymal transition (EMT) in human prostate cancer cell lines, and stable overexpression of miR-194 enhanced metastasis of intravenous and intraprostatic tumor xenografts. Conversely, inhibition of miR-194 activity suppressed the invasive capacity of prostate cancer cell lines in vitro and in vivo. Mechanistic investigations identified the ubiquitin ligase Suppressor of Cytokine Signaling 2 (SOCS2) as a direct, biologically relevant target of miR-194 in prostate cancer. Low levels of SOCS2 correlated strongly with disease recurrence and metastasis in clinical specimens. SOCS2 downregulation recapitulated miR-194-driven metastatic phenotypes, whereas overexpression of a non-targetable SOCS2 reduced miR-194-stimulated invasion. Targeting of SOCS2 by miR-194 resulted in derepression of the oncogenic kinases FLT3 and JAK2, leading to enhanced ERK and STAT3 signaling. Pharmacological inhibition of ERK and JAK/STAT pathways reversed miR-194-driven phenotypes. The GATA2 transcription factor was identified as an upstream regulator of miR-194, consistent with a strong concordance between GATA2 and miR-194 levels in clinical specimens. Overall, these results offer new insights into the molecular mechanisms of metastatic progression in prostate cancer.
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Cancer research. 2016 Dec 23 [Epub ahead of print]
Rajdeep Das, Phillip A Gregory, Rayzel C Fernandes, Iza Denis, Qingqing Wang, Scott L Townley, Shuang G Zhao, Adrienne Hanson, Marie A Pickering, Heather K Armstrong, Noor A Lokman, Esmaeil Ebrahimie, Elai Davicioni, Robert B Jenkins, R Jeffrey Karnes, Ashley E Ross, Robert B Den, Eric A Klein, Kim N Chi, Hayley S Ramshaw, Elizabeth D Williams, Amina Zoubedi, Gregory J Goodall, Felix Y Feng, Lisa M Butler, Wayne D Tilley, Luke A Selth
Dame Roma Mitchell Cancer Research Laboratories, University of Adelaide., Centre for Cancer Biology, University of South Australia., Dame Roma Mitchell Cancer Research Laboratories, The University of Adelaide., Department of Radiation Oncology, University of Michigan., Dame Roma Mitchell Cancer Research Laboratories, Discipline of Medicine, University of Adelaide & Hanson Institute., SAHMRI, University of Adelaide., School of Paediatrics and Reproductive Health, University of Adelaide., School of Molecular and Biomedical Science, The University of Adelaide., GenomeDx Biosciences Inc., Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine., Department of Urology, Mayo Clinic., Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University., Department of Radiation Oncology, Thomas Jefferson University., Glickman Urological and Kidney Institute, Cleveland Clinic., Medical Oncology, BC Cancer Agency., Centre of Cancer Biology, University of South Australia., Australian Prostate Cancer Research Centre - Queensland, Queensland University of Technology., The Vancouver Prostate Centre, University of British Columbia., Radiation Oncology, UCSF., South Australian Health and Medical Research Institute, University of Adelaide, School of Medicine and Freemasons Foundation Centre for Men's Health., Dame Roma Mitchell Cancer Research Laboratories, The University of Adelaide .