Bioinformatics Analysis Of Heavy Metal Cadmium Induced Liver Cancer And Functional Verification Of Candidate Genes

Cadmium(Cd)is a heavy,non-essential metal widely distributed in the soil,water and the atmosphere.Once absorbed,it could bind to metallothionein and is stored in the solid organs.The accumulation of Cadmium could facilitate its toxic effects on cells on account of deficiency of mechanisms by which Cadmium is excreted out.The liver is the first line of defense for human detoxification,with a large amount of absorbed Cd stored in.evidence indicates that exposure to Cd may be a risk factor for liver cancer,but their associations were uncertain.Still,the mechanisms are yet unknown.To explore the molecular mechanisms by which Cd induces liver malignant transformation,we have conducted the following research.First,we assessed the association of Cd levels in the body with liver cancer risk using evidence-based approaches;Second,using bioinformatics methods,we screened the genes that may play critical roles in Cd induced liver carcinoma,and further evaluate their roles;Third,we investigated the roles of the candidate genes via laboratory research.In Part One,Eleven publications comprising fourteen independent studies were selected for analysis and the overall pooled data showed that Cadmium levels were markedly higher in liver cancer patients than those in healthy controls(SMD=2.00;95%CI=1.20-2.81;p<0.05).To get a precise estimation,the subgroup analyses showed that Cadmium levels in serum and hair were significantly higher in liver cancer patients than those in the healthy controls,respectively.In Part Two,we screened out the differentially expressed genes(DEGs)from the dataset GSE64041 that concerned liver carcinoma.Then,DEGs regarding Cd-treated liver cells were screened out from GSE8865 and GSE31286.To obtain the DEGs that might be involved in Cd-induced liver cancer,the intersection of the above DEGs was aquired.As a result,the three genes,namely,LRAT,ITGA2 and SLC7A11 were included in the intersection.Through validation in Oncomine database,we found that ITGA2 and SLC7A11 except for LRAT were overexpressed in liver carcinoma tissues compared with healthy liver tissues.Analyzing the data of a TCGA cohort,we found that SLC7A11 is a prognostic factor for liver cancer.In Part Three,the mRNA and protein expressions of ITGA2 and SLC7A11 were elevated after treatment of low-concentration of Cd chloride in a cell model investigation.Using immunohistochemistry-based tissue microarrays,we validated the protein expressions of ITGA2 and SLC7A11 in liver cancer tissues.The results showed that overexpresson of ITGA2 and SLC7A11,respectively,were detected in liver cancer tissues relative to non-cancer tissues.The expression of SLC7A11 was negatively correlated with the pathological grade of liver cancer.Both ITGA2 and SLC7A11 mighit be the prognostic factor for liver carcinoma,respectively.Through the above research,we firstly obtained convincible evidence regarding the association between Cd levels in the body and liver cancer risk.Then,ITGA2 and SLC7A11 were screened out as candidate genes that may play critical roles in Cd-induced liver cancer by using bioinformatic methods.Afterwards,these two genes have been indicated to be an independent prognositic factor for liver cancer,respectively.The data suggested that ITGA2 and SLC7A11 may play important roles in Cd-induced malignant transformation of liver cells,and they have the potential to be targets for cancer therapy.