MicroRNA expression signature of castration-resistant prostate cancer: the microRNA-221/222 cluster functions as a tumour suppressor and disease progression marker

Abstract

Background:Our present study of the microRNA (miRNA) expression signature in castration-resistant prostate cancer (CRPC) revealed that the clustered miRNAs microRNA-221 (miR-221) and microRNA-222 (miR-222) are significantly downregulated in cancer tissues. The aim of this study was to investigate the functional roles of miR-221 and miR-222 in prostate cancer (PCa) cells.Methods:A CRPC miRNA signature was constructed by PCR-based array methods. Functional studies of differentially expressed miRNAs were analysed using PCa cells. The association between miRNA expression and overall survival was estimated by the Kaplan–Meier method. In silico database and genome-wide gene expression analyses were performed to identify molecular targets regulated by the miR-221/222 cluster.Results:miR-221 and miR-222 were significantly downregulated in PCa and CRPC specimens. Kaplan–Meier survival curves showed that low expression of miR-222 predicted a short duration of progression to CRPC. Restoration of miR-221 or miR-222 in cancer cells revealed that both miRNAs significantly inhibited cancer cell migration and invasion. Ecm29 was directly regulated by the miR-221/222 cluster in PCa cells.Conclusions:Loss of the tumour-suppressive miR-221/222 cluster enhanced migration and invasion in PCa cells. Our data describing targets regulated by the tumour-suppressive miR-221/222 cluster provide insights into the mechanisms of PCa and CRPC progression.

miRNAs as novel biomarkers in the management of prostate cancer

“…Several miRNAs (miR-21, miR-31, miR-34 and miR-124) can regulate the androgen receptor expression, and simultaneously, AR can regulate the expression of several miRNAs (miR-21, miR-27a, miR-34, miR-125b, miR-221 and let-7) [65]. Goto et al [66] recently demonstrated that miR-221 and 222 were significantly downregulated in CRPC specimens, even when this cluster was previously described to be upregulated ( Figure 3) [67,68]. This fact shows the dynamic status of miRNAs in the development of PCa, regulating the same miRNA different targets depending on the point of the cancer progression.…”

Regulation of HMGB3 by antitumor miR-205-5p inhibits cancer cell aggressiveness and is involved in prostate cancer pathogenesis

“…Interestingly, genes targeted by these miRNA passenger strands (SPOCK1, MELK, NCAPG, BUB1, and CDK1) were overexpressed in naive PCa and CRPC specimens and high expression of these genes predicted poor survival in patients with PCa [18]. Analyses of our signatures revealed that miR-205-5p was significantly downregulated in naive PCa and CRPC specimens [16,17]. Our previous study showed that restoration of miR-205-5p inhibited cancer cell aggressiveness through its targeting of centromere protein F (CENPF).…”

“…Based on this strategy, we have addressed antitumor miRNAs and associated cancer pathways in naive PCa and CRPC cells [16,17]. For example, miR-26a, miR-26b, miR-218, the miR-29-family, and miR-223 were downregulated in naive PCa tissues and these miRNAs inhibited cancer cell migration and invasion through targeting of genes involved in the extracellular matrix [27][28][29][30].…”

“…We have undertaken the identification of antitumor miRNAs, with the goal of determining how these miRNAs mediate gene expression networks in PCa cells [16][17][18]. The starting point of our strategy of miRNA studies is to identify aberrantly expressed miRNAs based on miRNA expression signatures [17][18][19][20][21].…”

“…The starting point of our strategy of miRNA studies is to identify aberrantly expressed miRNAs based on miRNA expression signatures [17][18][19][20][21]. Analyses of our miRNA signatures of PCa and CRPC have revealed that miR-205-5p is downregulated in cancer tissues [16][17][18]22].…”