MicroRNA-466 inhibits tumor growth and bone metastasis in prostate cancer by direct regulation of osteogenic transcription factor RUNX2

Melissa Colden, Altaf A. Dar, Sharanjot Saini, Priya V. Dahiya, Varahram Shahryari, Soichiro Yamamura, Yuichiro Tanaka, Gary Stein, Rajvir Dahiya, Shahana Majid

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere2572
JournalCell Death and Disease
Volume8
Issue number1
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

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Bone Development
MicroRNAs
Prostatic Neoplasms
Transcription Factors
Neoplasm Metastasis
Neoplasms
Bone and Bones
Prostate
Growth
Cell Line
Osteopontin
Osteocalcin
Kaplan-Meier Estimate
Vimentin
Cell Cycle Checkpoints
Heterografts
Computer Simulation
Cell Movement
Down-Regulation
Cell Proliferation

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

MicroRNA-466 inhibits tumor growth and bone metastasis in prostate cancer by direct regulation of osteogenic transcription factor RUNX2. / Colden, Melissa; Dar, Altaf A.; Saini, Sharanjot; Dahiya, Priya V.; Shahryari, Varahram; Yamamura, Soichiro; Tanaka, Yuichiro; Stein, Gary; Dahiya, Rajvir; Majid, Shahana.

In: Cell Death and Disease, Vol. 8, No. 1, e2572, 01.01.2017.

Research output: Contribution to journalArticle

Colden, M, Dar, AA, Saini, S, Dahiya, PV, Shahryari, V, Yamamura, S, Tanaka, Y, Stein, G, Dahiya, R & Majid, S 2017, 'MicroRNA-466 inhibits tumor growth and bone metastasis in prostate cancer by direct regulation of osteogenic transcription factor RUNX2', Cell Death and Disease, vol. 8, no. 1, e2572. https://doi.org/10.1038/cddis.2017.15
Colden, Melissa ; Dar, Altaf A. ; Saini, Sharanjot ; Dahiya, Priya V. ; Shahryari, Varahram ; Yamamura, Soichiro ; Tanaka, Yuichiro ; Stein, Gary ; Dahiya, Rajvir ; Majid, Shahana. / MicroRNA-466 inhibits tumor growth and bone metastasis in prostate cancer by direct regulation of osteogenic transcription factor RUNX2. In: Cell Death and Disease. 2017 ; Vol. 8, No. 1.
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