title: MicroRNA-194 Promotes Prostate Cancer Metastasis by Inhibiting SOCS2.
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 linesin vitroandin vivoMechanistic 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 ofSOCS2correlated 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.Cancer Res; 77(4); 1021-34. ©2016 AACR.
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, The University of Adelaide, South Australia, Australia.|Freemasons Foundation Centre for Men's Health, School of Medicine, The University of Adelaide, South Australia, Australia.
authors.forename: Rajdeep
authors.initials: R
authors.lastname: Das
authors.affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia.|School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Gregory
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, The University of Adelaide, South Australia, Australia.|Freemasons Foundation Centre for Men's Health, School of Medicine, The University of Adelaide, South Australia, Australia.
authors.forename: Rayzel C
authors.initials: RC
authors.lastname: Fernandes
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, The University of Adelaide, South Australia, Australia.|Freemasons Foundation Centre for Men's Health, School of Medicine, The University of Adelaide, South Australia, Australia.
authors.forename: Iza
authors.initials: I
authors.lastname: Denis
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, The University of Adelaide, South Australia, Australia.|Breast Cancer Genetics Group, Centre for Personalised Cancer Medicine, School of Medicine, The University of Adelaide, SA 5005, Australia.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, The University of Adelaide, South Australia, Australia.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Townley
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Shuang G
authors.initials: SG
authors.lastname: Zhao
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, The University of Adelaide, South Australia, Australia.
authors.forename: Adrienne R
authors.initials: AR
authors.lastname: Hanson
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, The University of Adelaide, South Australia, Australia.
authors.forename: Marie A
authors.initials: MA
authors.lastname: Pickering
authors.affiliation: Freemasons Foundation Centre for Men's Health, School of Medicine, The University of Adelaide, South Australia, Australia.|Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
authors.forename: Heather K
authors.initials: HK
authors.lastname: Armstrong
authors.affiliation: Research Centre for Reproductive Health, School of Paediatrics and Reproductive Health, Robinson Institute, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Noor A
authors.initials: NA
authors.lastname: Lokman
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, The University of Adelaide, South Australia, Australia.
authors.forename: Esmaeil
authors.initials: E
authors.lastname: Ebrahimie
authors.affiliation: GenomeDx Biosciences Inc., Vancouver, British Columbia, Canada.
authors.forename: Elai
authors.initials: E
authors.lastname: Davicioni
authors.affiliation: Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jenkins
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, Minnesota.
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Karnes
authors.affiliation: Department of Urology, Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Ross
authors.affiliation: Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Den
authors.affiliation: Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Klein
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.|Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Kim N
authors.initials: KN
authors.lastname: Chi
authors.affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Hayley S
authors.initials: HS
authors.lastname: Ramshaw
authors.affiliation: Australian Prostate Cancer Research Centre Queensland, Translational Research Institute, Princess Alexandra Hospital, Queensland University of Technology, Brisbane, Australia.
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Williams
authors.affiliation: The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Amina
authors.initials: A
authors.lastname: Zoubeidi
authors.affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia.|School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Goodall
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.|Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.|Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors.forename: Felix Y
authors.initials: FY
authors.lastname: Feng
authors.affiliation: Freemasons Foundation Centre for Men's Health, School of Medicine, The University of Adelaide, South Australia, Australia.|Cancer Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Butler
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, The University of Adelaide, South Australia, Australia.|Freemasons Foundation Centre for Men's Health, School of Medicine, The University of Adelaide, South Australia, Australia.
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Tilley
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories, School of Medicine, The University of Adelaide, South Australia, Australia. luke.selth@adelaide.edu.au.|Freemasons Foundation Centre for Men's Health, School of Medicine, The University of Adelaide, South Australia, Australia.
authors.forename: Luke A
authors.initials: LA
authors.lastname: Selth
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D050989:GATA2 Transcription Factor / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D050796:STAT3 Transcription Factor / Q000502:physiology; D050826:Suppressor of Cytokine Signaling Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; C554846:MIRN194 microRNA, human; D035683:MicroRNAs; C106643:SOCS2 protein, human; D050796:STAT3 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins