Construction of a Competing Endogenous RNA Network and Identification of Potential Regulatory Axes in Gastric Cancer Chemoresistance

Abstract Background: The development of chemoresistance is one of the leading causes of chemotherapy failure in gastric cancer (GC). Emerging evidence highlights the multifunctional role of noncoding RNAs (ncRNAs) in GC chemoresistance. However, the comprehensive expression profile and competing endogenous RNAs (ceRNAs) regulatory network between ncRNAs and mRNAs in GC chemoresistance remain unanswered.Methods: GC cell line MGC-803 was employed to create cisplatin-resistant MGC-803/DDP cells by continuous exposure to increasing doses of cisplatin. The whole-transcriptome sequencing (RNA sequencing) was performed to comprehensively analyze the differentially expressed (DE) lncRNAs, miRNAs and mRNAs in MGC-803/DDP and MGC-803 cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to investigate the biological functions implicated with the DEncRNAs. Then, the cisplatin-resistant-related ceRNA network and potential regulatory axes were constructed by bioinformatic analysis.Results: We successfully generated cisplatin-resistant GC cell line MGC-803/DDP. Differential expression analysis showed that a total of 1,936 DElncRNAs, 2,194 DEmRNAs and 174 DEmiRNAs were identified. Functional enrichment analysis indicated that those DEncRNAs were mainly involved in neuroactive ligand-receptor interaction, drug metabolism, Hippo signaling pathway, cAMP pathway and P53 pathway. Subsequently, the cisplatin-resistant-related ceRNA network consisting of 71 DElncRNAs, 121 DEmRNAs and 8 DEmiRNAs was constructed with the widely accepted vital chemo-resistant-related genes and signaling pathways. In addition, two constructed regulatory axes (include FAM66C/miR-129-5p/7 mRNAs and SFTA1P/miR-206/FN1 or NRP1) were successfully validated by the Genomic Data Commons (GDC) GC data.Conclusion: Our study has shown that differentially expressed ncRNAs have complex and intricate interactions in the cisplatin resistance of GC. The novel ceRNA network and the potential regulatory axes may provide the most comprehensive view of GC chemoresistance to date. Our findings uncovered potential biomarkers for prognostic prediction and novel therapeutic targets for reversing cisplatin resistance in GC.