Abstract
The main challenge in the treatment of prostate cancer (PCa) is that the majority of patients inevitably develop resistance to androgen deprivation. However, the mechanisms involved in hormone independent behavior of PCa remain unclear. In the present study, we identified androgen-induced miR-135a as a direct target of AR. Functional studies revealed that overexpression of miR-135a could significantly decrease cell proliferation and migration, and induce cell cycle arrest and apoptosis in PCa. We identified RBAK and MMP11 as direct targets of miR-135a in PCa by integrating bioinformatics analysis and experimental assays. Mechanistically, miR-135a repressed PCa migration through downregulating MMP11 and induced PCa cell cycle arrest and apoptosis by suppressing RBAK. Consistently, inverse correlations were also observed between the expression of miR-135a and RBAK or MMP11 in PCa samples. In addition, low miR-135a and high RBAK and MMP11 expression were positively correlated with PCa progression. Also, PI3K/AKT pathway was confirmed to be an upstream regulation signaling of miR-135a in androgen-independent cell lines. Accordingly, we reported a resistance mechanism to androgen deprivation therapy (ADT) mediated by miR-135a which might be downregulated by androgen depletion and/or PI3K/AKT hyperactivation, in castration-resistant prostate cancer (CRPC), thus promoting tumor progression. Taken together, miR-135a may represent a new diagnostic and therapeutic biomarker for castration-resistant PCa.
Highlights
Prostate cancer (PCa) is the second leading cause of cancer-related deaths in males with 27,540 attributed cases in the United States in 2015 [1]
PI3K/AKT pathway was confirmed to be an upstream regulation signaling of miR-135a in androgen-independent cell lines
MiR-135a expression levels increased more than 15 fold after high dose of DHT (1000 nM) stimulation compared with control (Figure 1C)
Summary
Prostate cancer (PCa) is the second leading cause of cancer-related deaths in males with 27,540 attributed cases in the United States in 2015 [1]. A few miRNAs including miR-125b [9], miR-21 [10], miR-32 [11] and miR-449 [12] were identified as androgen-responsive transcripts. In previous miRNA microarray analysis, we investigated an AR-microRNA-mRNA network[13] that regulated PCa cell viability, including miR-19a, miR-27a and miR-133b [14]. Part of these miRNAs had shown association with transformation to androgenresistant PCa [9,10,11]. Kroiss and his colleagues identified miR-135a as an androgen-upregulated miRNA [15]
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