New transcriptomics biomarkers involved in Cisplatin-flurouracil resistance in gastric cancer

Abstract

Abstract Resistance to Cisplatin-Fluorouracil (CF) combination therapy is the main obstacle in the treatment of Gastric Cancer (GC). Here we conducted a differential expression and differential co-expression study on a gene expression data set of initially responsive GC patients who show acquired resistance following sufficient exposure to CF. Concerted down-regulation of several genes associated with stabilizing gastrointestinal mucosa, along with several membrane proteins, were identified in resistant samples. A series of systems biology approaches were subsequently applied on the list of identified differentially expressed genes. Inspection of the constructed microRNA-gene network resulted in the identification of two up-regulated microRNAs, hsa-miR-520c-3p and hsa-miR-421, which negatively regulate the expression of three tumor suppressor genes; CXCL14, LEFTY1 and ZFP36L2. Differential co-expression analysis also revealed the expression concordance between RPRM, a critical contributor in cell cycle arrest, and splicing related genes including GPKOW, PQBP1 and DDX1 in resistant samples, emphasizing the role of alternative splicing in acquiring resistance in CF therapy. We believe that the results of this study can help to uncover the underlying mechanisms of CF resistance development. Following further experimental validation, the identified biomarkers can possibly be used as chemotherapy response predictors in GC patients receiving a CF chemotherapy regimen.