Expression Of CDH3/P-cadherin In Pancreatic Adenocarcinoma Patients And Its Clinical Significance

Aims:To find differential expression genes(DGEs)between pancreatic adenocarcinoma(PA)and normal pancreatic tissues(NPT),and to explore relations hips between DEGs and prognosis and clinicopathologic characteristics.Then,preliminar y study about the cause of gene differential expression was carried out.Methods:The Oncomine database and its analytic tool were used to find DGEs between PA and NPT,and target DEG(tDEG)was selected based on analytic results of Oncomine and literature search results.Then,PA GSEs from GEO(Gene Expression Omnibus)were adopted to validate the differential expression of tDGE.Clinicopathologic data,mRNA expression,protein expression and promoter methylation data were extracted from the TCGA(The Cancer Genome Atlas)database to analyze relationships between tDGE expression and prognostic as well as clinicopathologic factors.The prognostic value of tDGE was further validated by PA GSEs from GEO database.Data of PA patients undergoing surgery and patients receiving pancreaticoduodenectomy because of inferior bile duct or duodenum disease in our hospital and brother hospital were collected.Immunohistochemical(IHC)method was adopted to analyze tDGE expression in PA and NPT.Then,relations hips between tDGE expression and prognosis as well as clinicopathologic factors were analyzed to validate the findings from the database analysis.Results:Oncomine identified CDH3/P-cadherin as the top one DGE between PA and NPT based on 9 PA versus normal pancreatic tissue datasets,and the differentia l expression of CDH3/P-cadherin between PA and paired normal pancreatic tissue was validated by three GSEs of GEO database(GSE62452,GSE15471 and GSE16515),which meant that CDH3/P-cadherin expression level in PA was significantly higher than that of normal pancreatic tissue.Furthermore,IHC results of patients in our hospital and brother hospital showed that CDH3/P-cadherin expression was positive in88.5%PA patients(54/61),while none of 13 normal pancreatic tissues expressed CDH3/P-cadherin.There were 154 patients in TCGA mRNA cohort,with 100 and 54patients in CDH3/P-cadherin high and low expression groups respectively,and CDH3/P-cadherin expression was an independent risk factor of OS(P=0.036,HR:1.672,95%CI:1.034-2.705)and DFS(P=0.034,HR:1.742,95%CI:1.042,2.912).The1 year-,2 year-,and 3 year-OS rates were 67.2%,28.0%and 22.2%respectively in high expression group,while 88.3%,46.2%and 37.7%in low expression group.The 1year-,2 year-and 3 year-DFS rates were 51.6%,17.5%and 9.1%respectively in high expression group,while 75.2%,36.0%and 25.2%in low expression group.Similar results were found in CDH3/P-cadherin protein cohort.Two GSEs from GEO database also validated prognostic value of CDH3/P-cadherin expression(GSE57495 and GSE78229).Among 61 PA patients in our hospital and brother hospital,there were 22and 39 patients in high and low expression groups respectively,and CDH3/P-cadherin expression was an independent risk factor of OS(HR=2.900,95%CI:1.227-6.585,P=0.011).Analysis results of both the TCGA mRNA and protein cohorts demonstrated that CDH3/P-cadherin expression was related to R1 rate,and R1 rate was significa ntly higher in high expression group than in low expression group(19.0%VS 9.3%,P=0.036;48.8%VS 21.4%,P=0.041).Analysis results of patients in our hospital or brother hospital showed that CDH3/P-cadherin expression was correlated with adjacent organ invasion rate,and adjacent organ invasion rate of high expression group was significantly higher than that of low expression group(68.2%VS 28.2%,P=0.000).Analysis results of both the TCGA mRNA and protein cohorts demonstrated that CDH3/P-cadherin expression level was negatively correlated with promoter methylation level(r_s=-0.060,P=0.000;r_s=-0.395,P=0.000).Conclusions:CDH3/P-cadherin was differentially expressed between PA and normal pancreatic tissue,and the CDH3/P-cadherin expression level was significantly higher in PA than in normal pancreatic tissue,which was caused by CDH3 gene promoter hypomethylation.CDH3/P-cadherin expression was an independent risk factor of OS and DFS in PA patients after surgery,and was closely related to aggressive biologica l behaviors of PA.CDH3/P-cadherin can be used as a biomarker evaluating prognosis of PA patients and malignant degree of PA.