Upregulated ONECUT2 impeded the efficacy of 5-FU treatment to relapsed patients and might be an emerging indicator of chemotherapy in gastric cancer

Abstract

Background Chemotherapeutic resistance is a main obstacle for prolonging the lifetime of gastric cancer (GC) patients, so new emerging solutions still remain to be investigated. We aim to identify an effective target, ONECTU2, for chemotherapy of GC patient, particularly relapsed patients.Methods STAD patients matched with clinical features and transcriptome sequencing data from TCGA were used in this study. Gene set enrichment analyses (GSEA) were performed using 100 patients who were divided average according to ONECUT2 level. Cytotoxic assays for 5-FU and cisplatin were used to test the role of chemotherapeutic resistance of ONECUT2 in GC cells. 30 relapsed patients with previously resected tumor samples were collected to validate the efficacy of ONECUT2 in GC chemotherapy.Results ONECUT2 was a crucial regulator of Disease-Free Interval (DFI) in GC patients with reoccurrence once having chemotherapeutic treatment. Gene set enrichment analysis (GSEA) results suggest that upregulated ONECUT2 is positively correlated with the increased ability of xenobiotic drug metabolism, which might contribute to the pharmaceutical resistance in GC. Targeting ONECUT2 reduced half-maximal inhibitory concentration (IC50) of 5-FU and cisplatin in GC cells. The efficacy of 5-FU treatment was negatively correlated with ONECUT2 mRNA level of tumor samples derived from GC patients who relapsed after surgical resection.Conclusions These findings indicate that ONECUT2 displays a drug-resistant function in GC, providing a new therapeutic target for GC treatment.