Integrated bioinformatics analysis identified lncRNA-miRNA-mRNA competing endogenous RNA networks (ceRNA) that might be involved in prostate cancer progression to castration resistance

LEDESMA-BAZÁN, SABRINA; GUERON, GERALDINE; VAZQUEZ, ELBA; CASCARDO, FLORENCIA; COTIGNOLA, JAVIER

Mar del Plata

Congreso; LXVII REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA; 2022

SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA

Long non-coding RNAs (lncRNAs) regulate several biochemical pathways and contribute to the pathophysiology of cancer. We have previously identified 12 lncRNAs whose expression respond to hormone therapy in prostate cancer patients. Furthermore, in castration-resistant prostate cancer (CRPC), their levels were restored to those observed in therapy-naïve primary tumors. However, how these lncRNAs contribute to tumorigenesis is yet to be understood. Considering that lncRNAs might be sponges of miRNAs, we aimed at identifying lncRNA-miRNA-mRNA networks altered during prostate cancer progression. We performed a bioinformatics-based analysis using public datasets comprising 40 primary prostate tumors (11 paired pre- and post-androgen deprivation therapy (ADT) and 29 pre-ADT) and 8 CRPC. We identified 105 mRNAs differentially expressed in both post- vs pre-ADT primary tumors and CRPC vs post-ADT. Next, to create possible lncRNA-miRNA-mRNA networks, we used miRNet (a miRNA-centric network visual analytics platform) to seek miRNAs that target both lncRNAs and mRNAs. Of note, we found that PCGEM1 (lncRNA) expression correlates with ASPM (mRNA) expression (r=0.51, p=8.2E-13), and these two RNAs have target sequences for the binding of hsa-miR-506-3p and hsa-miR-124-3p. These results identified a possible PCGEM1-hsa-miR-506-3p/hsa-miR-124-3p-ASPM ceRNA involved in prostate cancer progression to castration resistance. In addition, Gene Set Variation Analysis (GSVA) revealed that this ceRNA network might regulate Wnt signaling pathway in prostate tumors. Other ceRNAs identified included RAB3B mRNA (RAS oncogene family) and are: PCGEM1-hsa-miR-124-3p-RAB3B, LINC01087-hsa-miR-130a-3p-RAB3B, and LINC01671-hsa-miR-145-5p-RAB3B. These results give new insights in ceRNA dysregulation in prostate cancer; and ultimately, they might help to identify new prognostic biomarkers for prostate cancer and new druggable targets for avoiding/delaying progression to CRPC.