Prostate cancer (PCa) is one of the most common causes of cancer-related deaths in men worldwide. Therefore, more specific and non-invasive diagnostic biomarkers as well as novel therapeutic targets are urgently needed. As miRNAs have been proposed as promising elements for the identification of novel diagnostic and therapeutic tools for different pathologies, including cancer, we investigated the miRNA landscape in PCa and explored their putative diagnostic/therapeutic utility. Specifically, the miRNome of plasma samples from healthy (n = 18) and PCa patients (n = 19) was initially determined using an Affymetrix-miRNA array. The main changes were validated in two independent cohorts (n = 296 and n = 84) by quantitative real-time PCR. Additionally, in silico and in vitro assays in normal and tumor prostate cell lines were performed. Results from the array revealed that the expression of 104 miRNAs was significantly altered (P < 0.01) in plasma samples from PCa patients compared with healthy controls. Of note, 6 of these miRNAs also exhibited a significant ROC curve to distinguish between healthy and PCa patients with an AUC equal to 1. A systematic validation using two independent cohorts of patients demonstrated that miR-107 was the most profoundly altered miRNA in PCa (P < 0.0001) exhibiting an AUC equal to 0.75. Interestingly, miR-107 significantly outperformed the ability of PSA to distinguish between control and PCa patients, as well as between non-significant (Gleason Score = 6) and significant (Gleason Score ≥ 7) PCa patients, being its expression correlated with relevant clinical parameters (e.g. PSA and testosterone levels, tumor volume). Remarkably, all these comparisons were even stronger in obese patients (BMI > 30). Interestingly, we found that miR-107 levels were also dysregulated in PCa tissues (compared to non-tumor tissues) and in PCa cells (compared to non-tumor cells). Moreover, in vitro overexpression of miR-107 significantly reduced cell proliferation, migration and tumorsphere formation in PCa cells, and altered the expression of several genes critical in PCa pathophysiology, such as FASN and CPT2 (implicated in cellular lipid metabolism), SRRM1, SRSF2 and TIA1 (involved in splicing process). Altogether, our data demonstrate that miR-107 might represent a new diagnostic and potential therapeutic tool in PCa, especially in patients under obesity condition.
MINECO (PID2019–105564RB-I00/FPU16–06190/FPU17–00263), ISCIII (PI16–00264/PI17–02287), Junta de Andalucía (BIO-0139) and CIBERobn.
22 May 2021 - 26 May 2021