Impact of novel miR-145-3p regulatory networks on survival in patients with castration-resistant prostate cancer

Abstract

Background:Despite recent advancements, metastatic castration-resistant prostate cancer (CRPC) is not considered curative. Novel approaches for identification of therapeutic targets of CRPC are needed.Methods:Next-generation sequencing revealed 945–1248 miRNAs from each lethal mCRPC sample. We constructed miRNA expression signatures of CRPC by comparing the expression of miRNAs between CRPC and normal prostate tissue or hormone-sensitive prostate cancer (HSPC). Genome-wide gene expression studies and in silico analyses were carried out to predict miRNA regulation and investigate the functional significance and clinical utility of the novel oncogenic pathways regulated by these miRNAs in prostate cancer (PCa).Results:Based on the novel miRNA expression signature of CRPC, miR-145-5p and miR-145-3p were downregulated in CRPC. By focusing on miR-145-3p, which is a passenger strand and has not been well studied in previous reports, we showed that miR-145-3p targeted 4 key molecules, i.e., MELK, NCAPG, BUB1, and CDK1, in CPRC. These 4 genes significantly predicted survival in patients with PCa.Conclusions:Small RNA sequencing for lethal CRPC and in silico analyses provided novel therapeutic targets for CRPC.

Molecular pathogenesis of renal cell carcinoma: Impact of the anti‐tumor miR‐29 family on gene regulation

“…Based on our original miRNA expression signatures, including that for RCC, we have identified RNA networks that are controlled by anti‐tumor miRNAs in several cancers . Downregulation of the miR‐29 family ( miR‐29a , miR‐29b and miR‐29c ) was frequently observed in many types of cancers .…”

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

“…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]. More recently, we showed that passenger strands of miRNAs, e.g., miR-150-3p and miR-145-3p acted as antitumor miRNAs in naive PCa and CRPC [18,31]. 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].…”

“…More recently, we showed that passenger strands of miRNAs, e.g., miR-150-3p and miR-145-3p acted as antitumor miRNAs in naive PCa and CRPC [18,31]. 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].…”

“…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].…”