Deregulation of miRNAs in malignant pleural mesothelioma is associated with prognosis and suggests an alteration of cell metabolism

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive human cancer and miRNAs can play a key role for this disease. In order to broaden the knowledge in this field, the miRNA expression was investigated in a large series of MPM to discover new pathways helpful in diagnosis, prognosis and therapy. We employed nanoString nCounter system for miRNA profiling on 105 MPM samples and 10 healthy pleura. The analysis was followed by the validation of the most significantly deregulated miRNAs by RT-qPCR in an independent sample set. We identified 63 miRNAs deregulated in a statistically significant way. MiR-185, miR-197, and miR-299 were confirmed differentially expressed, after validation study. In addition, the results of the microarray analysis corroborated previous findings concerning miR-15b-5p, miR-126-3p, and miR-145-5p. Kaplan-Meier curves were used to explore the association between miRNA expression and overall survival (OS) and identified a 2-miRNA prognostic signature (Let-7c-5p and miR-151a-5p) related to hypoxia and energy metabolism respectively. In silico analyses with DIANA-microT-CDS highlighted 5 putative targets in common between two miRNAs. With the present work we showed that the pattern of miRNAs expression is highly deregulated in MPM and that a 2-miRNA signature can be a new useful tool for prognosis in MPM.

Figure 1

Heat map representing hierarchical clustering of 63 statistically significantly deregulated miRNAs detected in the present work on 96 MPM and 10 control tissues. Rows: miRNAs; columns: samples; red: high expression; blue: low expression.

Figure 2

Kaplan-Meyer curves representing the correlation between 2-miRNA signature based on Let-7c-5p and miR-151a-5p expression levels and overall survival rates in MPM patients. High levels (grey line) of Let-7c-5p plus miR-151a-5p were associated with a significantly worse overall survival than low levels (black line) in patients recruited in the present study (A), in the TCGA mesothelioma dataset (B) and in an independent set of fresh frozen MPM (C) (P = 0.004, P = 0.021, and P = 0.038, respectively).