Predictive and Prognostic Value of an MicroRNA Signature for Gastric Carcinoma Undergoing Adjuvant Chemotherapy.

Abstract

Gastric carcinoma (GC) is one of the most common cause of tumor-related death. Chemotherapy resistance usually occurs, leading to cancer relapse and poor survival of GC patients. To investigate the role of miRNAs in chemotherapy resistance for GC patients, we conducted an integrated analysis of miRNA expression and survival information using data obtained from The Cancer Genome Atlas project. Genome-wide screening of chemotherapy response-specific miRNAs was performed using Cox proportional hazards regression analyses for patients who received chemotherapy or those who had never received chemotherapy, respectively. A four-miRNA expression signature (involving two protective miRNAs, miR-200b and miR-103a, and two risk ones miR-199 and miR-152) was predicted as a specific indicator for GC chemoresistance (p = 0.00053; hazard ratio = 8.63), outperforming those clinicopathological factors. Functional experiments confirmed the roles of these signature miRNAs in regulation of chemotherapy response. Functional enrichment of these signature miRNAs and risk score revealed positive association with epithelial-mesenchymal transition (EMT), and negative association with cell cycle checkpoint and DNA damage response. Furthermore, the immune infiltration-miRNA functional network analysis revealed transformation from activated effector cells to resting immunosuppressive cells are preferred in GCs with adverse chemotherapy response. In summary, our work identifies a four-miRNA expression signature as a promising chemoresistance biomarker in GC, which provides novel insights into developing new strategies to overcome GC chemoresistance.