title: MicroRNA-466 inhibits tumor growth and bone metastasis in prostate cancer by direct regulation of osteogenic transcription factor RUNX2.
abstract: MicroRNAs (miRNAs) have emerged as key players in cancer progression and metastatic initiation yet their importance in regulating prostate cancer (PCa) metastasis to bone has begun to be appreciated. We employed multimodal strategy based on in-house PCa clinical samples, publicly available TCGA cohorts, a panel of cell lines, in silico analyses, and a series of in vitro and in vivo assays to investigate the role of miR-466 in PCa. Expression analyses revealed that miR-466 is under-expressed in PCa compared to normal tissues. Reconstitution of miR-466 in metastatic PCa cell lines impaired their oncogenic functions such as cell proliferation, migration/invasion and induced cell cycle arrest, and apoptosis compared to control miRNA. Conversely, attenuation of miR-466 in normal prostate cells induced tumorigenic characteristics. miR-466 suppressed PCa growth and metastasis through direct targeting of bone-related transcription factor RUNX2. Overexpression of miR-466 caused a marked downregulation of integrated network of RUNX2 target genes such as osteopontin, osteocalcin, ANGPTs, MMP11 including Fyn, pAkt, FAK and vimentin that are known to be involved in migration, invasion, angiogenesis, EMT and metastasis. Xenograft models indicate that miR-466 inhibits primary orthotopic tumor growth and spontaneous metastasis to bone. Receiver operating curve and Kaplan-Meier analyses show that miR-466 expression can discriminate between malignant and normal prostate tissues; and can predict biochemical relapse. In conclusion, our data strongly suggests miR-466-mediated attenuation of RUNX2 as a novel therapeutic approach to regulate PCa growth, particularly metastasis to bone. This study is the first report documenting the anti-bone metastatic role and clinical significance of miR-466 in prostate cancer.
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, CA, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Colden
authors.affiliation: CPMC Research Institute, San Francisco, CA, USA.
authors.forename: Altaf A
authors.initials: AA
authors.lastname: Dar
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, CA, USA.
authors.forename: Sharanjot
authors.initials: S
authors.lastname: Saini
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, CA, USA.
authors.forename: Priya V
authors.initials: PV
authors.lastname: Dahiya
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, CA, USA.
authors.forename: Varahram
authors.initials: V
authors.lastname: Shahryari
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, CA, USA.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Yamamura
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, CA, USA.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Biochemistry and Surgery, University of Vermont College of Medicine, 148 Beaumont Avenue, Burlington, VT, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Stein
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, CA, USA.
authors.forename: Rajvir
authors.initials: R
authors.lastname: Dahiya
authors.affiliation: Department of Urology, VA Medical Center and UCSF, San Francisco, CA, USA.
authors.forename: Shahana
authors.initials: S
authors.lastname: Majid
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000378:metabolism; D001859:Bone Neoplasms / Q000556:secondary*; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D010012:Osteogenesis / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; D050659:Core Binding Factor Alpha 1 Subunit; C585904:MIRN466 microRNA, human; D035683:MicroRNAs; C493709:RUNX2 protein, human