Ming Mechanism And Potential Therapeutic Drugs For Cisplatin Resistant Ovarian Cancer Based On Bioinformatics

Objectives:To investigate the feasibility of probing into the mechanisms and potential therapeutic drugs on drug resistance ovarian cancer by bioinformatics methods. The effect of potential therapeutic drug on the growth of cisplatin resistant ovarian cancer cells were verified by experiments.Methods:GSE15372 containing five cisplatin sensitive samples and five cisplatin resistance samples which were retrieved from the GEO database. Differentially expressed genes (DEGs) were identified by R and Bioconductor software. DAVID was used to perform Gene Ontology (GO) enrichment analysis and pathway enrichment analysis of the identified DEGs. The PPI pairs of the screened DEGs were analyzed using the STRING, the PPI network construction using Cytoscape software. At the same time, the Map Connectivity module in the Enrichr platform was used to dig out the candidate drugs for drug resistance to cisplatin, then analysis the resistance mechanisms of candidate drugs. In vitro cisplatin resistance in ovarian cancer cell COC1/DDP, use MTT method to detect the different time and different concentration of sanguinarine on cell proliferation.Results:1.Totally 759 differentially expressed genes were obtained by using R and Bioconductor software through analyze the data set of GSE15372, among them 454 genes were up regulated and 305 genes were down regulated.2. The resistant ovarian carcinoma differentially expressed genes of GO biological analysis and KEGG pathway were analysed by using DAVID.454 differentially up regulated expressed genes were mainly involved in cell cycle,cholesterol biosynthesis process, DNA copy, sterol biosynthesis process, DNA metabolism, cholesterol metabolism process, steroids biosynthesis.process of diverse biological functions mainly involved in cell cycle, the citric acid cycle (TCA cycle), copy, proteasome, steroid synthesis and triterpene skeleton compounds biosynthesis pathway.305 down regulation genes mainly involved in mesenchymal cell development, mesenchymal cell differentiation, development of quality, enzyme linked protein protein receptor signal transduction pathway and multiple biological functions.which Mainly involved in proteoglycans in cancer and oxytocin signaling pathway.3.We found up-regulated expression genes key target proteins for ACLY, CDK2, CCNB1, HSP90AA1, CDC6, AURKB, ORC1, MCM5, BUB1, MCM7, CCNA2, ACTA2, MCM4, MCM6, RRM2 and down-regulated expression genes key target proteins for JUN, EGFR, FOX, FGF2, ITGA2 through the STRING and Cytoscape analysis.4. The potential drug candidates for cisplatin resistance including sanguinarine, azacitidine, trichostatin A, vorinostat and etoposide by using bioinformatics tool enrichment in connectivity map.5.The related different expression genes of sanguinarine were analysed, which were JUN, MT2A, TSAN13, CXADR, DUSP1, MMP1, ESRP1, FOSB, KLF4, AREG, ATF3. Sanguinarine played an important role on drug resistance ovarian cancer cells through the ErbB signaling pathway which involved in JUN, AREG genes.6.Sanguinarine can inhibit the growth of cisplatin resistant ovarian cancer cell line of COC1/DDP compared with the control group (P<0.05). The Inhibition ability were different in diverse concentrations and diverse time, the inhibitory ability increased with the increase of time and drug concentration.Conclusions:1.759 differentially expressed genes in cisplatin resistant ovarian cancer were screened out, and the biological function annotation and pathway analysis of up regulation and down regulated genes were carried out, which provided theoretical basis for the study of the disease.2.Successfully constructed a protein interaction networks of cisplatin resistant ovarian carcinoma differentially expression genes, and identify the key target genes, it is helpful to further study the interaction of differentially expressed genes. The research direction is provided for the diagnosis and treatment of the disease.3.The potential therapeutic drug and mechanism of drug resistant ovarian cancer can be excavated by bioinformatics method, and the method is reasonable, simple and convenient, and can reduce the blindness of drug development research.4.Sanguinarine can inhibits ovarian cancer drug resistant cells growth, which is expected to use in the resistant ovarian cancer. It was worthy to be researched further.