Impacts Of Stat3-IL-17 Signaling Pathway On The Progression Of Gastritis,gastric Intraepithelial Neoplasia,gastric Cancer And Prognosis

Objective: By detecting the tissue levels of Stat3/IL-17 signaling pathway molecules in combination with p53 and Ki-67 molecules in gastritis,gastric intraepithelial neoplasia(GIN)and gastric cancer(GC)patients,and analyzing the impact of the dynamic levels on the natural course and survival prognosis,this study aims to explore the possibility to develop a quantifiable method that may be used in clinics to predict prognosis for GC patients after surgery.Methods:(1)Patients(n=70,534 cases)biopsied under gastroscopy for the first time were identified in the database from the Department of Pathology,the First Affiliated Hospital of Shihezi University School of Medicine from November 2007 to December 2017,among which 109 GC cases had surgically resected tissues.From a pool of 36,401 cases,13,962 cases were followed-up for multiple gastroscopic biopsies among which 71 cases with gastric cancer presented with continuous disease progression from gastritis to gastric cancer.The dynamic tissue levels of p-Stat3,IL-17,p53 and Ki-67 in gastritis,GIN and GC were tested using immunohistochemistry(IHC)method.Statistical analyses used were Kruskal-Wallis H test,Spearman rank method,ROC-defined AUC(area under the curve)and univariate logistic regression methods.(2)Patient database was established using Excel spreadsheets and statistical analyses were performed using the SPSS(version 22.0)software package.(3)69 patients with gastric cancer undergoing radical gastrectomy were followed-up until October 2018.Patients’ overall survivals in association with TNM stages and tissue levels of the IHC-tested molecules were analyzed using Cox regression analysis,One-factor ROC curve,Logistic combined multivariate ROC curve,or Kaplan-Meier survival analysis.Results:(1)Among patients with gastritis,GIN and gastric cancer,their tissue levels of p-Stat3,IL-17,p53 and Ki-67 were significantly different(P<0.001),and the increased levels were positively correlated with the severity of the diseases.There was a positive correlation between disease classification and p-Stat3,IL-17,p53 or Ki-67(P<0.01).High tissue levels of activated p-Stat3 and of expressed IL-17,p53 and Ki-67 were risk factors for gastric cancer prognosis(P<0.01).Preoperative indicators(age,BMI,cell differentiation,p-Stat3,IL-17,p53 and Ki-67)and postoperative indicators(T,N,M,and TNM stage)were all correlated with survival prognosis in gastric cancer patients.(2)Analyses of survival prognosis among69 postoperative patients with gastric cancer showed the following results: 1)Tissue levels of p-Stat3,IL-17,p53,Ki-67 were correlated with GC patients’ survival.2)Among them,the predictive effectiveness(AUC values)of IL-17 was the highest among all bio-indicators tested.3)Survival analyses by combining three molecular indicators,the predictive survival viability for the combination of IL-17,Ki-67 and p53(IL-17+Ki-67+p53)was the strongest with an AUC of 0.869(95% CI=0.787,0.950),which was much higher than that of TNM staging with an AUC of 0.829(95% CI=0.726,0.929)(P<0.05)in predicting prognosis for gastric cancer patients.Kaplan-Meier analyses showed that the cumulative survival rates for patients with predictive low death risk(PLR)were as high as 89.7% while only 30.0% for patients with predictive high death risk(PHR),and the difference was a dramatic 59.7%.Conclusions:(1)The dynamic levels of p-Stat3,IL-17,p53 and Ki-67 are different in the natural course of gastric diseases from gastritis to GIN to gastric cancer,i.e.,the more serious the disease progression,the higher the tissue levels of those above molecules.(2)High levels of activated p-Stat3 and of expressed IL-17,p53,and Ki-67 are risk factors for the prognosis in patients with gastric cancer.(3)ROC-defined AUC values are a quantified measurement for risk factors which can be cross-compared in prognostic analyses.(4)Interestingly,combined levels of bio-indicators IL-17+p53+Ki-67 show stronger predictive capability than the standard TNM staging system in predicting death risks for postoperative patients with GC.Because IL-17,p53 and Ki-67 can be tested preoperatively,these findings may provide practical guidance in personalized surgical planning before surgery and the optimal follow-up intervals after surgery for patients with GC who need surgical treatment.