Small Extracellular Vesicle-Derived microRNAs Stratify Prostate Cancer Patients According to Gleason Score, Race and Associate with Survival of African American and Caucasian Men

Abstract

The utility of small extracellular vesicles (sEVs)-derived microRNAs (miRs) to segregate prostate cancer (PCa) patients according to tumor aggressiveness and ancestral background has not been fully investigated. Thus, we aimed to determine the diagnostic and prognostic utility of sEV-associated miRs in identifying aggressive PCa in African American (AA) and Caucasian (CA) men. Using a training cohort, miR profiling was performed on sEVs isolated from plasma of PCa patients. Top-ranked sEV-associated miRs were then validated in 150 plasma samples (75 AA and 75 CA) collected from two independent cohorts; NIH (n = 90) and Washington University (n = 60) cohorts. Receiver operating characteristic (ROC) curve, Kaplan–Meier and Cox proportional hazards regression were used to assess these miRs as clinical biomarkers. Among nine top-ranked sEV-associated miRs, miR-6068 and miR-1915-3p were enriched in sEVs collected from PCa patients compared to healthy volunteers. Moreover, miR-6716-5p and miR-3692-3p segregated AA from CA men and low from high Gleason score (GS), respectively. Upregulation of sEV-associated miR-1915-3p, miR-3692-3p and miR-5001-5p was associated with improved survival time, and only miR-1915-3p was associated with longer recurrence-free survival (RFS) as an independent prognostic marker. Taken together, we identified novel sEV-associated miRs that can differentiate PCa patients from normal, AA from CA and high from low GS and predicts RFS.

MiRNA biomarkers in cancers of the male reproductive system: Are we approaching clinical application?

“…Remarkably, miR‐375‐3p levels in plasma samples of 252 patients before undergoing curative‐intent treatment independently predicted metastasis‐free survival and identified patients who would develop metastases with 50% sensitivity and 76% specificity 48 . Moreover, miRNA profiling on plasma‐derived EVs identified mir‐1915‐3p as an independent predictor of recurrence‐free survival 49 …”

Dietary stilbenes as modulators of specific miRNAs in prostate cancer

“…The data regarding the functions and exact roles of identified stilbene-regulated miRNAs in prostate cancer are incomplete and require further studies. Upregulation was linked to recurrence-free survival Ali et al (2021) Independent prognostic marker a These miRNAs are putative stilbene-regulated oncosuppressor miRs previously identified by Dhar et al, 2011. Frontiers in Pharmacology frontiersin.org…”

“…Interesting results were reported on the overexpression of spermidine synthase (SRM) in prostate cancer tissues and miR-1908-mediated regulation of SRM, which controls the secretion of extracellular vesicles (EV) in prostate cancer ( Urabe et al, 2020 ). Finally, upregulation of EV-associated miR-1915-3p was concomitant with improved survival time along with two other miRs, but only miR-1915-3p was associated with longer recurrence-free survival as an independent prognostic marker in prostate cancer patients with low and high Gleason scores and of various races ( Ali et al, 2021 ). It is important to notice that detailed experimental mechanistic studies to prove biological consequences of stilbene modulated oncosuppressive miRs in prostate cancer are lucking.…”

Exploring new frontiers in prostate cancer research: Report from the 2022 Coffey−Holden prostate cancer academy meeting

“…15,16 Fortunately, new research deciphering the molecular profiles and tumor biology of AA prostate cancers suggests that AA patients may have a unique biological phenotype of prostate cancer and host immunity that could impact antitumor immune response or response to emerging targeted therapies. [17][18][19] More research into the factors that contribute to prostate cancer disparities, and a better understanding of barriers to health equity are major areas of needed research.…”

“…However, most of these treatments are based on tumor characteristics and their vulnerabilities from studies in populations composed primarily of non‐Hispanic European American men, which may not benefit underrepresented populations like African American (AA) patients 15,16 . Fortunately, new research deciphering the molecular profiles and tumor biology of AA prostate cancers suggests that AA patients may have a unique biological phenotype of prostate cancer and host immunity that could impact antitumor immune response or response to emerging targeted therapies 17–19 . More research into the factors that contribute to prostate cancer disparities, and a better understanding of barriers to health equity are major areas of needed research.…”