Alterations in microRNA expression profiles may be implicated in increased prevalence of cancer in Sertoli cell-only syndrome cases: A systematic review and in-silico analysis

Study question Could microRNA dysregulation be an underlying molecular mechanism leading to the observed increased prevalence of cancer in patients with Sertoli-cell only syndrome (SCOS)? Summary answer Patients with SCOS are characterized by altered microRNA profiles and dysregulated gene pathways involved in SCOS pathophysiology and in cell-cycle control and therefore in carcinogenesis. What is known already Sertoli cell-only syndrome constitutes a histopathological subtype of non-obstructive azoospermia, affecting 26.3–57.8% of azoospermia patients. It is characterized by partial or complete absence of active spermatogenesis due to germ cell aplasia. Except from infertility, SCOS is associated with increased risk of testicular nodules and cancer, rendering research on the topic essential. Despite advances, the underlying molecular mechanisms connecting SCOS with cancer remain unknown. Data demonstrates that microRNAs could play crucial roles in both SCOS pathophysiology and carcinogenesis. Identifying relevant microRNAs and conducting in-silico analysis on affected pathways may lead to mapping the way forward. Study design, size, duration A systematic review was performed in PubMed/Medline and Embase up to April 2022. Only full-length original studies in humans were included. Strict inclusion-exclusion criteria were applied aiming to select studies comparing microRNA profiling between SCOS cases versus men with normal spermatogenesis or men with proven fertility. Following study selection, data on altered microRNA expression patterns were analyzed to underline differences between the abovementioned groups. Subsequently, in-silico functional analysis was performed to compare affected gene pathways. Participants/materials, setting, methods The studied population consisted of SCOS cases. Men with normal spermatogenesis or proven fertility served as the control group. Predicted microRNA–target pairs were retrieved from microT-CDS, while a 0.8 cutoff threshold was applied. The GTEx repository was used to identify microRNA-targeted genes in the testis. Annotations derived from Ensembl and miRbase. Gene-set enrichment analysis was performed employing the KEGG-database. Fisher’s exact test was performed in R package limma, setting a 0.01 p-value threshold. Main results and the role of chance Four studies reported altered microRNA expression profiles in SCOS (n = 45) versus normal spermatogenesis cases or men of proven fertility (n = 16). Functional analysis revealed that six microRNAs, which were downregulated in the SCOS cases, namely hsa-miR-34b-5p, hsa-miR-202-3p, hsa-miR-34c-5p, hsa-miR-449a, hsa-miR-141-3p, and hsa-miR-34b-3p, affected 66 statistically significant gene-targets in the testis. Two pathways were reported to be statistically significantly dysregulated from these microRNAs, namely the ‘’microRNAs in cancer’’ pathway (40 affected genes, p-value = 0.004), and the ‘’TGF-beta signaling’’ pathway (26 affected genes, p-value = 0.01). Furthermore, four microRNAs, namely hsa-miR-10b-5p, hsa-miR-4270, hsa-miR-181c-5p, and hsa-miR-605-3p, reported to be upregulated in the SCOS group. These microRNAs had 108 statistically significant gene-targets in the testis. Three pathways were statistically significantly dysregulated from these microRNAs, namely the ‘’Herpes simplex virus 1 infection’’ pathway (61 affected genes, p-value = 0.01), the ‘’microRNAs in cancer’’ pathway (28 affected genes, p-value = 0.01), and the ‘’longevity regulating’’ pathway (19 affected genes, p-value = 0.01). The molecular role of the affected gene pathways in proper cell-cycle regulation and germ cell differentiation is herein underlined as critical. In the disrupted testicular microenvironment of the SCOS cases these disrupted genes may act as inducers of carcinogenic mechanisms. Limitations, reasons for caution The main limitation is the small number of the included studies and the small number of participants investigated per study, especially with regards to the control group. Moreover, the observed heterogeneity among the studies regarding the molecular tools employed for the microRNA profiling is another reason for caution. Wider implications of the findings Our data suggest that the dysregulation of microRNAs affecting several gene pathways that control cell-cycle and differentiation may lead to increased cancer risk in SCOS cases. Further studies employing our findings as a starting point will indicate whether microRNA profiling can serve as an effective evaluation tool for cancer predisposition. Trial registration number Not applicable