The Prognosis Of SERPINE2 Expression In Gastric Cancer And Its Molecular Dynamics Simulation As A Potential Therapeutic Target

Objective: As one of the most common malignant tumors in the world,the incidence and mortality of gastric cancer remain high.Most patients lack effective targeted drugs at present,and the overall prognosis is still very poor.Therefore,it is of great significance to study the prognosis evaluation and targeted therapy of gastric cancer patients.Serpine inhibitor E2(SERPINE2)is a member of the serine protease inhibitor superfamily.Many studies have shown that the expression of SERPINE2 is closely related to the occurrence and development of tumors.Studying the role of SERPINE2 in gastric cancer provides clues for finding new therapeutic targets and developing more effective therapeutic strategies.Methods: Four GSE data sets of gastric cancer were screened to explore the prognosisrelated genes of gastric cancer,and SERPINE2 was found to be a potential key biomarker.Data related to gastric cancer were downloaded from TCGA databases,and the expression of SERPINE2 in different histological types was analyzed,and the correlation between the expression of SERPINE2 and clinical features and prognosis was analyzed.The mechanism of SERPINE2 in gastric cancer was explored by pathway enrichment analysis,mi RNA correlation analysis,methylation correlation analysis and copy number variation analysis.The potential therapeutic drugs with high expression of SERPINE2 in gastric cancer were screened by CMap database.Autodock vina software was used to carry out molecular docking between the screened drugs and SERPINE2 protein,and the drugs with the most stable binding to the protein were selected.Gromacs software was used for molecular dynamics simulation to analyze the dynamic conformational changes of SERPINE2-drug ligand complex and model verification.SERPINE2 mutation data were downloaded from the genome website of National Cancer Institute,and the effects of mutation on the structure and function of SERPINE2 protein and its ligand binding ability were explored by IMutant2.0 analysis and molecular dynamics simulation.MM-PBSA method was used to calculate the binding free energy of the molecular simulation system after it reached stability,and the total binding free energy of the system was decomposed into single residues for analysis.Results: The expression of SERPINE2 gene in TCGA database was significantly higher in gastric cancer tissues than in normal tissues,and the high expression of SERPINE2 was significantly related to OS and RFS.Pathway enrichment analysis showed that the high expression group of SERPINE2 mainly enriched to tumors and other related pathways;The association analysis between the high and low expression groups of SERPINE2 and mi RNA suggests that some micro RNAs down-regulate the expression of SERPINE2 and thus promote the invasion and metastasis of gastric cancer.Methylation correlation analysis suggested that hypomethylation of CPG island was beneficial to the expression of SERPINE2;The gene enrichment analysis with significant changes in copy number shows that it is related to cancer-related pathways.Nineteen candidate drugs for the treatment of gastric cancer were screened by CMap,and the drug with the lowest binding energy and stable binding was MAZ51 through batch molecular docking.Molecular dynamics simulation verified that SERPINE2-MAZ51 complex showed certain stability in the simulation process,and RMSF suggested that the structure fluctuation of residues located in the binding cavity was low,indicating that the continuous interaction of the complex could stabilize the related structures.Hydrogen bonding plays a key role in the combination of complexes.SERPINE2 A71 V mutation site is located in the binding pocket of protein,and molecular dynamics simulation proves that this mutation affects the binding stability of SERPINE2-MAZ51.The binding free energy of SERPINE2-MAZ51 calculated by MMPBSA method is-141.681 k J/mol,and the binding affinity is very strong.VAL122,ILE119 and ILE111 are the key residues involved in the binding process of the complex,and the binding strength of the complex is also affected by ALA71 site.Conclusion: SERPINE2 is a oncogene of gastric cancer,and its high expression indicates a bad prognosis.MAZ51 is more effective in patients with gastric cancer with high expression of SERPINE2,and the mutation of SERPINE2 A71 V will reduce the efficacy.