| Background:Esophageal squamous cell carcinoma(ESCC)has obvious regional and gender differences,suggesting the particularity of its etiology.Environmental factors are considered to be the main cause of malignant tumors,but the relationship between class I human carcinogen cadmium(Cd)and ESCC is still controversial.Chaoshan area is one of the six high-incidence areas of esophageal cancer(EC)in China and it is the only coastal area with high incidence of EC,local environmental pollution and relatively unique dietary habits here caused higher risk level of daily Cd exposure.The relationship between blood Cd load and the occurrence,development and prognosis of ESCC in Chaoshan population needs to be explored.Our recent studies had shown that chronic low-concentration Cd exposure promotes the malignant biological phenotype of ESCC cell lines,whether Cd regulates the expression of key genes in cancer signaling pathways through long non-codingRNA(IncRNA)should be explored as epigenetic changes are one of the carcinogenic mechanisms of Cd.Objective:The aim of the study is to explore the relationship between Cd exposure and Morbidity risk,clinicopathological characteristics and prognosis of ESCC in Chaoshan area,and we tried to explore its carcinogenic mechanism as well.Material and methods: For this analysis,150 patients with confirmed ESCC were recruited as the case group,with an average age of 59±10 years old,and 177 control groups were recruited with an average age of 57.47±14.12 years old between May 2001 to June 2020.General demographic and clinical pathological information,follow-up information and other data were collected through electronic medical records.A total of 2m L fasting venous blood was collected by venipuncture,and Cdconcentrations in whole bloodwere measured by inductively coupled plasma mass spectrometry(ICP-MS).Chronic Cd-treated ESCC cell line 109(CCT1-EC-109)was induced by a12-week treatment with 1μM Cd Cl2 in ESCC cell line 109(EC-109),Whole transcriptome sequencing was performed for CCT1-EC-109 and EC-109.All analyses were conducted by SPSS 19.0(SPSS Inc.,Chicago,IL,USA),Graph Pad Prism 8.0(Graph Pad,San Diego,CA)and R language software.Differences between groups were tested by t-test,Mann-Whitney U test.Spearman correlation analysis and logistic regression analysis were used to evaluate the relationship between blood Cd levels(BCLs)and risk and clinicopathological characteristics of ESCC.K-M log-rank test and Cox proportional hazard regression model to evaluate the relationship between BCLs and progression-free survival(PFS).R package edge R was used for mRNA / lncRNA differential expression analysis,and blast was for lncRNA target gene prediction,GO and KEGG pathway enrichment analysis was carried by enrich R package.Results:The median BCLs in the case group was 2.60μg/L,higher than 1.63μg/L in the control group(P<0.001).Blood Cd is a risk factor for ESCC since ORs are 1.11(1.01,1.21)compared to controls,and there is a dose-response relationship between Cd exposure and risk of ESCC since trend chi-square test P<0.001.BCLs were positively correlated with smoking history(r = 0.386,P<0.01)and drinking history(r = 0.374,P<0.01),but were negatively correlated with disease history(r =-0.164,P<0.05)and gender(r =-0.399),P <0.01).Multivariate logistic regression analysis showed that the risk of high blood Cd in male patients was 16.86 times that of females(95% CI3.11-91.58,P= 0.001),while patients with high BMI index and disease history had a lower risk of high blood Cd(OR = 0.77,95% CI 0.64-0.93,P = 0.01,OR = 0.27,95% CI0.33-4.92,P = 0.01);K-M log-rank test showed that BCLs,gender,age,clinical stage,and N stage were all related to PFS(P<0.05),and Cox regression analysis suggested that BCLs,gender,and disease history(P=0.03,0.02,0.04)are independent risk factors that affect the prognosis of ESCC,but age(P=0.004)may be an independent protective factor.Whole transcriptome sequencing has identified 2794 differentially expressed lncRNAs that were related to Cd exposure and 2751 lncRNA-related target genes.The functional enrichment of GO and KEGG suggested that cancer-related pathways(such as the Hippo signaling pathway)mediatethe occurrence and development of ESCC.Conclusion:1.The BCLs of ESCC patients in Chaoshan area were significantly higher than controls and Cd exposure is one of the risk factors of ESCC in this area;2.BCLs of ESCC patients in Chaoshan area are closely related to gender,smoking history,drinking history,and BMI;3.High blood Cd load is an independent risk factor for disease progression and poor prognosis of ESCC in Chaoshan area;4.Cd may regulates Hippo and other cancer-related signal pathways through lncRNA-mRNA mechanism to mediates the development of ESCC. |
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