miR‐125b promotes growth of prostate cancer xenograft tumor through targeting pro‐apoptotic genes

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 prostate cancer. 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 prostate cancer 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 prostate cancer 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 prostate cancer.

MiR-125 in normal and malignant hematopoiesis

“…22 The upregulation of miR-125b was shown to be associated with the reduction of BCL2-antagonist/killer (BAK1), P53 and PUMA levels, all of which are known targets of miR-125b. 22,23 This is further supported by the fact that lowering miR-125b expression by androgen withdrawal was associated with an increase in BAK1, P53 and PUMA expression. 23 …”

“…22,23 This is further supported by the fact that lowering miR-125b expression by androgen withdrawal was associated with an increase in BAK1, P53 and PUMA expression. 23 …”

“…Whether or not P53 is a bona-fide target in all cell types and species, miR-125b was demonstrated to target other components of the P53 pro-apoptotic network, including BAK1, PUMA, BMF, TRP53INP1 and Kruppel-like factor 13 (KLF13). 22,23,25,27,42,[56][57][58][59] All were shown to be direct targets of miR-125b in more than one system and cell type (Figure 4).…”

CFTR mediates bicarbonate-dependent activation of miR-125b in preimplantation embryo development

“…The expression of miR-125b is also found in mouse preimplantation embryos although its exact role has not been eluciated [16]. Several proteins, including p53, have been reported to be the targets of miR-125b and mediate its action in various physiological and pathological events, including neuronal differentiation [12,17,18], immune response [19,20] and cancer [10,[21][22][23]. Particularly, p53 has been reported to mediate the effect of miR-125b on embryo development [15].…”

The miRNA-kallikrein axis of interaction: a new dimension in the pathogenesis of prostate cancer

“…In order to create a comprehensive list of miRNAs dysregulated in PCa, we combined data from our recently published miRNA microarray comparing PCa with normal matched prostate tissue from the same patient (Schaefer et al , 2010a ) and did a literature search for additional reported miRNAs dysregulated in PCa when compared to normal prostate tissue (Sylvestre et al , 2007 ;Ambs et al , 2008 ;Shi et al , 2011 ;Sun et al , 2011 ).…”