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Semen miRNAs Contained in Exosomes as Non-Invasive Biomarkers for Prostate Cancer Diagnosis.

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.

SUBMITTER: Barcelo M

PROVIDER: S-EPMC6760223 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Semen miRNAs Contained in Exosomes as Non-Invasive Biomarkers for Prostate Cancer Diagnosis.

Barceló Maria M Castells Manel M Bassas Lluís L Vigués Francesc F Larriba Sara S

Scientific reports 20190924 1

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 ...[more]

PMID: 31551516

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Project description:We looked for the presence of prostatic cells and RNAs (cellular and acellular) of prostatic origin in the ejaculate semen from fertile and sterilized men and from men with prostate cancer, to ascertain the suitability of ejaculate semen for studying and monitoring prostate health. Methods. For prostatic cells, semen from fertile and sterile men and men with prostate cancer were subjected to density gradient centrifugation on a 60% cushion of Suprasperm™ and fractions containing somatic cells were washed and cytospun onto coated slides prior to fixation and immunocytochemistry with antibodies recognizing prostatic markers. Small RNAs were isolated from liquefied semen clarified of all cellular and other insoluble material by high-speed ultra-centrifugation. Sequencing libraries were prepared from fractions isolated by PAGE, corresponding to small non-coding (snc) RNAs in the 18-23 nt and 30-35 nt size ranges. Libraries were interrogated by next generation sequencing and analysed to generate lists of differentially expressed RNAs associated with cancer and sterility. Results. Cells positive for cytokeratin 18, PSMA, NKX3.1 and CD24 were observed in most ejaculate samples by indirect immunocytochemistry as either discrete cellular entities or within clumps of cell containing material (DAPI+; antigen positive and negative) and cytoplasmic fragments (DAP–; antigen positive and negative). RNA from populations of cells enriched by differential density gradient centrifugation supported their immunocytochemical designation as prostatic cells. Small RNAs (18 - 43 nt) from seminal plasma were highly heterogeneous although tRNAs and 5SRNAs were the dominant forms. A degree of overlap between the respective differential expression profiles of small RNAs from sterile and cancer samples, suggested a common feature, perhaps indicating an inflammatory response. Conclusion. This study supports a wider appraisal of ejaculate semen for studying and monitoring prostate health.

Project description:PurposeThe analysis of exosome/microvesicle (extracellular vesicles (EVs)) and the RNA packaged within them (exoRNA) has the potential to provide a non-invasive platform to detect and monitor disease related gene expression potentially in lieu of more invasive procedures such as biopsy. However, few studies have tested the diagnostic potential of EV analysis in humans.Experimental designThe ability of EV analysis to accurately reflect prostate tissue mRNA expression was examined by comparing urinary EV TMPRSS2:ERG exoRNA from pre-radical prostatectomy (RP) patients versus corresponding RP tissue in 21 patients. To examine the differential expression of TMPRSS2:ERG across patient groups a random urine sample was taken without prostate massage from a cohort of 207 men including prostate biopsy negative (Bx Neg, n = 39), prostate biopsy positive (Bx Pos, n = 47), post-radical prostatectomy (post-RP, n = 37), un-biopsied healthy age-matched men (No Bx, n = 44), and young male controls (Cont, n = 40). The use of EVs was also examined as a potential platform to non-invasively differentiate Bx Pos versus Bx Neg patients via the detection of known prostate cancer genes TMPRSS2:ERG, BIRC5, ERG, PCA3 and TMPRSS2.ResultsIn this technical pilot study urinary EVs had a sensitivity: 81% (13/16), specificity: 80% (4/5) and an overall accuracy: 81% (17/21) for non-invasive detection of TMPRSS2:ERG versus RP tissue. The rate of TMPRSS2:ERG exoRNA detection was found to increase with age and the expression level correlated with Bx Pos status. Receiver operator characteristic analyses demonstrated that various cancer-related genes could differentiate Bx Pos from Bx Neg patients using exoRNA isolated from urinary EVs: BIRC5 (AUC 0.674 (CI:0.560-0.788), ERG (AUC 0.785 (CI:0.680-0.890), PCA3 (AUC 0.681 (CI:0.567-0.795), TMPRSS2:ERG (AUC 0.744 (CI:0.600-0.888), and TMPRSS2 (AUC 0.637 (CI:0.519-0.754).ConclusionThis pilot study suggests that urinary EVs have the potential to be used as a platform to non-invasively differentiate patients with prostate cancer with very good accuracy. Larger studies are needed to confirm the potential for clinical utility.

Project description:BackgroundImproved detection of hepatocellular carcinoma (HCC) is needed, as current detection methods, such as alpha fetoprotein (AFP) and ultrasound, suffer from poor sensitivity. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate many cellular functions and impact cancer development and progression. Notably, miRNAs are detectable in saliva and have shown potential as non-invasive biomarkers for a number of cancers including breast, oral, and lung cancers. Here, we present, to our knowledge, the first report of salivary miRNAs in HCC and compare these findings to patients with cirrhosis, a high-risk cohort for HCC.MethodsWe performed small RNA sequencing in 20 patients with HCC and 19 with cirrhosis. Eleven patients with HCC had chronic liver disease, and analyses were performed with these samples combined and stratified by the presence of chronic liver disease. P values were adjusted for multiple comparisons using a false discovery rate (FDR) approach and miRNA with FDR P < 0.05 were considered statistically significant. Differential expression of salivary miRNAs was compared to a previously published report of miRNAs in liver tissue of patients with HCC vs cirrhosis. Support vector machines and leave-one-out cross-validation were performed to determine if salivary miRNAs have predictive potential for detecting HCC.ResultsA total of 4,565 precursor and mature miRNAs were detected in saliva and 365 were significantly different between those with HCC compared to cirrhosis (FDR P < 0.05). Interestingly, 283 of these miRNAs were significantly downregulated in patients with HCC. Machine-learning identified a combination of 10 miRNAs and covariates that accurately classified patients with HCC (AUC = 0.87). In addition, we identified three miRNAs that were differentially expressed in HCC saliva samples and in a previously published study of miRNAs in HCC tissue compared to cirrhotic liver tissue.ConclusionsThis study demonstrates, for the first time, that miRNAs relevant to HCC are detectable in saliva, that salivary miRNA signatures show potential to be highly sensitive and specific non-invasive biomarkers of HCC, and that additional studies utilizing larger cohorts are needed.

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Semen miRNAs Contained in Exosomes as Non-Invasive Biomarkers for Prostate Cancer Diagnosis.

Publications

Semen miRNAs Contained in Exosomes as Non-Invasive Biomarkers for Prostate Cancer Diagnosis.

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