MicroRNA-194 promotes prostate cancer metastasis by inhibiting SOCS2

Rajdeep Das, Philip A. Gregory, Rayzel C. Fernandes, Iza Denis, Qingqing Wang, Scott L. Townley, Shuang G. Zhao, Adrienne R. 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. RamshawElizabeth D. Williams, Amina Zoubeidi, Gregory J. Goodall, Felix Y. Feng, Lisa M. Butler, Wayne D. Tilley, Luke A. Selth

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Serum levels of 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 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 nontargetable 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. Pharmacologic 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.

Original languageEnglish
Pages (from-to)1021-1034
Number of pages14
JournalCancer Research
Volume77
Issue number4
DOIs
Publication statusPublished - 15 Feb 2017
Externally publishedYes

Keywords

  • MicroRNA-194
  • Prostate Cancer Metastasis
  • SOCS2

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  • Cite this

    Das, R., Gregory, P. A., Fernandes, R. C., Denis, I., Wang, Q., Townley, S. L., Zhao, S. G., Hanson, A. R., Pickering, M. A., Armstrong, H. K., Lokman, N. A., Ebrahimie, E., Davicioni, E., Jenkins, R. B., Karnes, R. J., Ross, A. E., Den, R. B., Klein, E. A., Chi, K. N., ... Selth, L. A. (2017). MicroRNA-194 promotes prostate cancer metastasis by inhibiting SOCS2. Cancer Research, 77(4), 1021-1034. https://doi.org/10.1158/0008-5472.CAN-16-2529