MicroRNA Expression Analysis and Biological Pathways in Chemoresistant Non- Small Cell Lung Cancer

Alterations in DNA damage repair (DDR) pathways can impair cisplatin efficacy. MicroRNAs (miRNAs) are actively involved in DDR regulation and in parallel have been suggested as potential biomarkers for the prediction of response to platinum- based chemotherapy (CT) in non- small cell lung cancer (NSCLC). In the present study we used a bioinformatics approach to identify differentially expressed miRNAs associated with the efficacy of platinum-based chemotherapy in NSCLC. We assembled four miRNA microarray expression datasets from NSCLC patients treated with CT included in the Gene Expression Omnibus (GEO) repository. Analysis in Limma package in R revealed 3.883 differentially expressed (DE) miRNAs between responders (n=71) and non-responders (n=99). After meta-analysis by random-effects, we identified a total of 697 miRNAs that were consistently up or down-regulated in at least two studies. By using more stringent effect size thresholds, we identified 43 DE miRNAs with log fold change ≥1.3 in at least two datasets. The prognostic significance of the selected miRNAs was further validated through survival analysis by KM plotter in stage III NSCLC. Twenty-two of the DE miRNAs were revealed to have prognostic significance in NSCLC. Integrated function and target pathway enrichment analysis revealed significant associations to a number of pathways and functions related to DDR, such as p53, HIPPO and FOXO3. Finally, we extracted a miRNA signature consisting of 8-miRNAs (miR-181a, let-7g, miR-26a, miR-145, miR-30d, miR-99a, miR-214, miR-107) that were down-regulated in non-responders and are involved in at least three DDR pathways. Comparative expression analysis on tumor and matched normal tissues from operable NSCLC patients treated with platinum-based chemotherapy will be performed to evaluate the clinical relevance of the signature.