A Meta-analysis Of Statin Use And Gynecologic Cancer Risk And Study On The Role And Mechanisms Of Statin Use In Endometrial Cancer

Objective: The relationship between the use of statins and the risk of gynecologic cancers remain controversial for many years.The aim of this study was to investigate the relationship between statin use and gynecological cancer risk and to verify it through cellular experiments.At the same time,gene expression profiling data from GEO database were analyzed using bioinformatics tools to identify potential anti-cancer mechanisms.Methods: Two researchers independently searched the commonly used databases of China National Knowledge Infrastructure(CNKI),Wan Fang Data,China Science and Technology Journal Database(CSTJ)-CQVIP,Pub Med,Embase,and Cochrane Central Register of Controlled Trials(CENTRAL).All original comparative studies published both in English or Chinese that were related to statin use and risk of gynecologic cances were included.Data extracting and literature screening were carried out based on the criteria.The Cochrane risk of bias(Ro B)tool provided by the Cochrane Collaboration and the Newcastle–Ottawa scale(NOS)were used for evaluating the quality of the included literature.All analyses were performed using Revman 5.2 and Stata software version 12.0.Afterwards,Lovastatin,a lipophilic statin,was used to treat human endometrial cancer cells HEC-1A and ISK,and whether statins have inhibitory effects on endometrial cancer was verified by MTT cell proliferation assay,apoptosis assay and cell cycle assay.In addition,Dataset GSE59007 and GSE68986 were obtained from GEO database,analyzed by GEO2 R,differentially expressed genes were screened,DEGs(differentially expressed genes)were analyzed by GO analysis and KEGG pathway analysis using Metascape,and protein-protein interactions networks were constructed by STRING and Cytoscape to identify Hub genes,and potential anti-cancer mechanisms of statins were analyzed by the above methods.Results: 1.Statin use reduced overall gynecologic cancer risk(OR = 0.80,95% CI 0.69-0.93)and was more effective in preventing endometrial cancer risk(OR = 0.66,95% CI 0.52-0.85),but did not affect other specific types of gynecologic cancer such as cervical cancer(OR = 0.21,95% CI 0.01-4.29),vulvar cancer(OR = 0.50,95% CI 0.05-5.51)and ovarian cancer(OR = 0.89,95% CI 0.77-1.04).2.Long-term statin use(>5 years)did not reduce gynaecological cancer risk(OR = 0.93,95% CI 0.77-1.13).In the subgroup analysis based on study type,study location,study quality,percentage of cancer cases in the study population,etc.,the results were generally able to support the above conclusions.3.The results of MTT experiment showed that lovastatin effectively inhibited cell proliferation in a concentration-dependent manner in two types of endometrial cancer cells,HEC-1A and ISK,after 72 hours of treatment with different concentrations of lovastatin.4.The results of cell cycle experiments showed that lovastatin blocked both HEC-1A and ISK cells in the G0/G1 phase and reduced the number of cells in the S phase in a concentration-dependent manner after 24 hours of treatment with different concentrations of lovastatin.5.The results of cell cycle experiments showed that the percentage of early apoptotic cells in ISK cells and HEC-1A cells increased in a concentration-dependent manner after 24 hours of treatment with different concentrations of lovastatin.6.Statins can act as an anticancer agent by affecting cellular signalling pathways such as cell cycle,DNA replication,mismatch repair and nucleotide excision repair.Conclusions: 1.Statin use mildly reduces overall gynaecological cancer risk and endometrial cancer risk,but does not reduce the risk of other specific types of gynaecological cancer(e.g.,cervical,vulvar and ovarian cancer).2.Long-term use of statins(>5 years)does not reduce gynaecological cancer risk.3.The evidence for the preventive effect of statin use on overall gynaecological and endometrial cancer is suggestive but not conclusive. 4.Lovastatin effectively inhibited the proliferation of ISK cells and HEC-1A cells in a concentration-dependent manner.5.Lovastatin inhibits the proliferation of endometrial cancer cells by inducing apoptosis.6.The molecular mechanisms by which statins prevent endometrial cancer may be related to cellular signalling pathways such as the cell cycle pathway,DNA replication pathway,mismatch repair pathway and nucleotide excision repair pathway.