Influence of peripheral whole-blood microRNA-7 and microRNA-221 high expression levels on the acquisition of castration-resistant prostate cancer: evidences from in vitro and in vivo studies

Prostate cancer (PC) is the more frequently diagnosed neoplasia in men in developed countries. The evolution of PC to castration-resistant prostate cancer (CRPC) represents real problems of clinical management, in consequence to the limited therapeutic options. MicroRNAs (miRNAs) are small noncoding RNAs that play an important role in gene expression and function regulation. The increased evidence that miRNAs are involved in cancer development and progression has made them potential biomarkers for cancer diagnosis, prognosis, and aggressiveness. Our purpose was to identify a miRNA expression profile associated with the development of CRPC. We firstly observed a miRNA expression profile differentially expressed between the castration-resistant (CR) PC3 cell line and the hormone-sensitive LnCaP cell line, where miR-7, miR-221, and miR-222 were upregulated in PC3 (11.3-fold increase, P = 0.012; 11.3-fold increase, P = 0.002; 8.6-fold increase, P = 0.002, respectively). We also observed that the trend of miR-1233 expression levels was higher in PC3 (3.7-fold increase, P = 0.057). These miRNAs differentially expressed in vitro were studied in a peripheral whole-blood samples from PC patients. We observed that patients presenting an early CR acquisition (≤20 months) had higher expression levels of miR-7 and miR-221 (P = 0.034 and P = 0.036, respectively). Furthermore, we found that patients diagnosed with high-Gleason score tumors and presenting simultaneous higher miR-7 expression levels have a significant reduce time to CR compared with patients who present lower miR-7 expression levels (11 vs. 51 months, log-rank test P = 0.004). We also found that patients diagnosed with high-Gleason score tumors and higher expression levels of miR-221 have an early CRPC compared to patients with lower miR-221 expression levels (10 vs. 46 months, log-rank test P = 0.012). We observed a significantly lower overall survival in patients with higher peripheral whole-blood expression levels of miR-7 (28 vs. 116 months, log-rank test P = 0.001). Our results suggest that miR-7 and miR-221 peripheral whole-blood expression levels can be potential predictive biomarkers of CRPC development.