Abstract
Although it is specific for prostatic tissue, serum prostate-specific antigen (PSA) screening has resulted in an over-diagnosis of prostate cancer (PCa) and many unnecessary biopsies of benign disease due to a well-documented low cancer specificity, thus improvement is required. We profiled the expression level of miRNAs contained in semen exosomes from men with moderately increased PSA levels to assess their usefulness, either alone or in addition to PSA marker, as non-invasive biomarkers, for the early efficient diagnosis and prognosis of PCa. An altered miRNA expression pattern was found by a high throughput profiling analysis in PCa when compared with healthy individuals (HCt) exosomal semen samples. The presence of vasectomy was taken into account for the interpretation of results. Fourteen miRNAs were selected for miRNA validation as PCa biomarkers in a subsequent set of semen samples. In this explorative study, we describe miRNA-based models, which included miRNA expression values together with PSA levels, that increased the classification function of the PSA screening test with diagnostic and/or prognostic potential: [PSA + miR-142-3p + miR-142-5p + miR-223-3p] model (AUC:0,821) to discriminate PCa from BPH (Sn:91,7% Sp:42,9% vs Sn:100% Sp:14,3%); and [PSA + miR-342-3p + miR-374b-5p] model (AUC: 0,891) to discriminate between GS ≥ 7 tumours and men presenting PSA ≥ 4 ng/ml with no cancer or GS6 tumours (Sn:81,8% Sp:95% vs Sn:54,5% Sp:90%). The pathway analysis of predicted miRNA target genes supports a role for these miRNAs in PCa aetiology and/or progression. Our study shows semen exosome miRNA-based models as molecular biomarkers with the potential to improve PCa diagnosis/prognosis efficiency. As the next step, further prospective studies on larger cohorts of patients are required to validate the diagnostic and/or prognostic role of the miRNA panel before it could be adopted into clinical practice.
Highlights
Www.nature.com/scientificreports many unnecessary biopsies of benign disease; only about 30–40% of the biopsied men are diagnosed with prostate cancer (PCa) and in patients with prostate-specific antigen (PSA) levels of 4 to 10 ng/ml, the detection rate of PCa was merely 20% or less defining the region as a “grey zone”
The research is conceived as an assessment/development pilot study for a PCa biomarker test based on semen exosome miRNAs which was divided into two phases (Fig. 1)
All the benign prostatic hyperplasia (BPH) and PCa individuals included in this first phase presented PSA levels within the 4–6 ng/ml range (Supplementary Table S1)
Summary
Www.nature.com/scientificreports many unnecessary biopsies of benign disease; only about 30–40% of the biopsied men are diagnosed with PCa and in patients with PSA levels of 4 to 10 ng/ml, the detection rate of PCa was merely 20% or less defining the region as a “grey zone”. Serum PSA levels do not correlate with tumour aggressiveness, survival, or response to pharmacological treatments leading to over-treatment of indolent tumours Given this context, more specific non-invasive diagnostic biomarkers, either alone or in addition to PSA marker, that could identify PCa patients would be very welcomed . Prostasomes, and in general the exosomes in semen, have multiple physiological functions most of them related to the fertility process[17,18,19,20] Both neoplastic and metastatic PCa cells have been shown to release prostasomes[21,22,23], contributing to the spread and development of PCa. In the present study we explored the potential of exosome miRNAs in semen from men with moderately altered serum PSA levels as non-invasive biomarkers of PCa
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