Authors: 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
Summary:
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.
Source:
Cancer Research; 2016, canres.2529.2016