miR-125b promotes growth of prostate cancer xenograft tumor through targeting pro-apoptotic genes.
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 3'-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.


CONCLUSIONS
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.
Shi
Xu-Bao
XB
Department of Urology, University of California, Davis, School of Medicine, Sacramento, California 95817, USA.
Xue
Lingru
L
Ma
Ai-Hong
AH
Tepper
Clifford G
CG
Kung
Hsing-Jien
HJ
White
Ralph W deVere
RW
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019295:Computational Biology; D016158:Genes, p53; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D025521:Tumor Suppressor Proteins / Q000235:genetics; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; C494773:Bak1 protein, mouse; D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; C488588:PUMA protein, mouse; D025521:Tumor Suppressor Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein