The Prognosis Significance And Mechanism Of SIRT6 In Gastric Cancer

Objective: Gastric cancer(GC),is one of the most threatening cancer with the third and fifth rank in cancer deaths and frequencies worldwide.Especially in China,its incidence is the highest among different types of cancer.Despite a rapid development of diagnosis and treatments prolonging the overall survival of patients,the majority of patients are still in advanced stages at their initial diagnosis.The 5-year survival rate of most advanced patients was only 5% and they often died of the rapid multiple organ metastasis.Therefore,it’s essential to explore the sensitive and specific biomarkers for predicting the prognosis of patients with gastric cancer.Sirtuin proteins(SIRTs),are a family of NAD+-dependent histone deacetylases with highly evolution-conserved domains and variegated functions.There are seven members,SIRT1-7,in this protein family,identified to participate in aging,DNA damage repair,apoptosis,metabolism and cancer development.There is not much research between SIRTs and gastric cancer,and the prognostic analysis of large samples is lacking.In the previous studies,SIRT1,SIRT2 and SIRT7 have be proved to be the promotors of gastric cancer.However,Other famlily members ’ role in oncogenesis is still controversial.Therefore,it is of great significance to clarify the prognostic role and mechanism of SIRTs family in gastric cancer through online data analysis of large samples.In this study,GSE62254 gastric cancer data and TCGA databases were used to explore the prognostic role of the overall Sirtuin family in GC.the prognostic value of SIRT6,rather than other family members,was identified in both GSE62254 datasets and TCGA databases.The relationship between SIRT6 and other clinicopathological parameters in gastric cancer was analyzed in GSE62254 datasets.Furthermore,GSEA analysis combined with cell experiments explored the mechanism of SIRT6 in gastric cancer.The results provide new clues for clarifying the prognostic significance and mechanism of SIRT6 in gastric cancer.Methods:1.The correlation of SIRTs’ expression with prognosis in gastric cancer was analyzed using the Kaplan-Meier Plotter online website and COX regression.2.InGSE62254 and TCGA datasets,the impact of SIRT6 expression on the prognosis of gastric cancer was clarified using Kaplan-Meier analysis and Log-rank test.3.COX univariate / multivariate regression analysis was used to identify the indendent factors in gastric cancer among SIRT6 and otherclinicopathological parameters.The nomogram was established and validated based on the results of COX analysis.4.Chi-square test was used to analyze the relationship between SIRT6 expression and clinicopathological characteristics such as gender,age,T stage,N stage,M stage and Lauren subtypes.5.Gene Set Enrichment Analysis(GSEA)was performed to predict SIRT6-related pathway in gastric cancer.6.After SIRT6 knocked-down,the changes of migration ability and protein expression were detected by the transwell and Western blot,respectively.Results: 1.Low expression of SIRT6 rather than other Sirtuin family members,indicates a poor prognosis in gastric cancer.2.The expression of SIRT6 is suggested to be significantly positively correlated with the prognosis of gastric cancer in Both GEO and TCGA datasets.3.SIRT6 expression,T stage,N stage,and M stage are the independent prognostic factors in gastric cancer.Then,an independent factor nomogram model based on the independent predictive factors above was established well for the prognostic prediction in patients with GC.4.High-SIRT6 is markedly associated with the M0 stage and intestinal subtype.5.When knocking-down SIRT6 in gastric cancer cells,the cell migration ability was increased.6.The result of GSEA indicated that low expression of SIRT6 was closely related to KEGG＿WNT＿SIGNALING＿PATHWAY and KEGG＿REGULATION＿ACTIN＿CYTOSKELOTON.7.The phosphorylation level of inactivated β-catenin was decreased,and the expression of intergrin α5 was upregulated after the knocking-down of SIRT6.Conclusion: 1.The low expression of SIRT6 is related to the poor prognosis of gastric cancer and SIRT6 plays a protective role in gastric cancer prognosis.2.SIRT6 tends to be highly expressed in patients with gastric cancer in stage M0.3.The downregulation of SIRT6 could promote gastric cancer cell migration by activating Wnt pathway and upregulating of intergrin α5.