MicroRNA profiles of prostate cancer bone metastases and miR-375 as an inhibitor of the aggressive metastasis subtype MetB

Abstract

Novel treatments for metastatic prostate cancer (PC) are needed. Molecular subtypes of bone metastatic PC (MetA-C) were recently identified, with the proliferation-driven MetB subtype linked to very poor prognosis. Non-coding microRNAs (miRs) regulate gene expression and constitute potential therapeutic targets. This study aimed to explore miR profiles in bone metastases in relation to the MetA-C subtypes, with focus on the aggressive MetB subtype. Genome-wide microarray analysis of clinical bone metastasis samples (n = 96, 62 patients) identified miR-375 to be inversely associated with the MetB subtype. The metastatic C4-2B cell line was transduced to overexpress or sequester miR-375 and effects were evaluated by microarray analysis, cell proliferation/adhesion assays, and tumor growth in mice. miR-375 overexpression in C4-2B altered transcription profiles and shifted the phenotype from being MetB-like to becoming MetA-like. In cell culture, miR-375 overexpression reduced cell proliferation, increased adhesion, and downregulated YAP1 expression among other direct gene targets, while miR-375 inhibition had opposite effects. In mice, miR-375 overexpression reduced tumor establishment and growth. Our data link clinical and experimental findings of miR-375 being a potential inhibitor of the aggressive MetB subtype in PC.