MiR-125b promotes growth of prostate cancer xenograft tumor through targeting pro-apoptotic genes

Xu Bao Shi, Lingru Xue, Ai Hong Ma, Clifford G. Tepper, Hsing Jien Kung, Ralph W Devere White

Research output: Contribution to journalArticlepeer-review

145 Citations (Scopus)

Abstract

Background Increasing evidence demonstrates that aberrantly regulated microRNAs (miRNAs) contribute to the initiation and progression of human cancer. We previously have demonstrated that miR-125b stimulated the growth of prostate cancer (CaP) cells. In this study, we further determined the influence of miR-125b on the pathogenesis of CaP. Methods To evaluate the effect of miR-125b on xenograft tumor growth, male athymic mice were subcutaneously injected with PC-346C-miR-125b cells that stably overexpressed miR-125b. Potential direct target transcripts of miR-125b were identified using a bioinformatics approach and three miR-125b targeted molecules were confirmed by means of biochemical analyses. Results Enforced expression of miR-125b promoted tumor growth in both intact and castrated male nude mice. In an effort to define the molecular mechanism(s) mediating its tumor growth properties, we found that miR-125b directly targets eight transcripts, including three key pro-apoptotic genes: p53, Puma, and Bak1. Increasing the abundance of miR-125b resulted in a dramatic decrease in the levels of these three proteins in CaP cells. A direct repressive effect on each of these was supported by the ability of miR-125b to significantly reduce the activity of luciferase reporters containing their 3â-untranslated regions of each gene encompassing the miR-125b-binding sites. Additionally, we found that repression of miR-125b activity was able to sensitize CaP cells to different therapeutic interventions. Conclusion Data obtained in this study demonstrate that miR-125b promotes growth of prostatic xenograft tumors by down-regulating three key pro-apoptotic genes. This suggests that miR-125b is oncogenic and makes it an attractive therapeutic target in CaP. Prostate 77:538-549, 2011.

Original languageEnglish
Pages (from-to)538-549
Number of pages12
JournalProstate
Volume71
Issue number5
DOIs
Publication statusPublished - Apr 1 2011
Externally publishedYes

Keywords

  • microRNA
  • p53
  • pro-apoptotic gene
  • prostate cancer

ASJC Scopus subject areas

  • Urology
  • Oncology

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