G6PD And PFKFB3 Are Independent Biomarkers In TNM Stage Ⅲ-Ⅳ Gastric Cancer With Treatment Of XELOX

Objective: Glucose 6 Phosphate Dehydrogenase（G6PD）and 6-Phosphofructokinase-2/Fructose-2,6-Bisphosphatase（PFKFB3）are involved in multiple mechanisms of tumorigenesis.However,the association of clinical characteristics with the expression and prognosis of G6 PD and PFKFB3 in gastric cancer（GC）are still studied limited.The current study aimed to explore the function of G6 PD and PFKFB3 as biomarkers in GC.Methods: Immunohistochemical staining and quantitative real-time PCR（q RT-PCR）were used to verify the expression levels of G6 PD and PFKFB3 in GC and normal gastric tissues of different TNM stages.In addition,the overall survival（OS）and disease-free survival（DFS）of GC patients with different G6 PD and PFKFB3 expression levels were detected by Kaplan-Meier and Log-rank.At the same time,the potential of G6 PD and PFKFB3 to predict prognosis was further analyzed using univariate and multivariate Cox regression models.Results: Immunohistochemical staining showed that the expression levels of G6 PD and PFKFB3 were significantly up-regulated in GC patients with TNM stages III-IV compared with normal human gastric tissues.However,there was no significant change in GC patients with TNM stage I-II.At the same time,the expression levels of G6 PD and PFKFB3 were correlated with histological grade（P=0.001;P=0.014）,preoperative carcinoembryonic antigen（CEA）level（P=0.031;P=0.001）and lymph node metastasis（P=0.001;P=0.014）in GC patients.P=0.020;P=0.002)were significantly correlated.It was further determined by real-time quantitative PCR results that the expression levels of G6 PD and PFKFB3 were also significantly up-regulated in GC patients with TNM stages III-IV compared with human normal gastric tissues.However,there was no significant change in GC patients with TNM stage I-II.In addition,Kaplan-Meier and Log-rank tests found high expression levels of G6 PD and PFKFB3 in TNM stage III-IV GC patients,their OS（P=0.015;P=0.008）and DFS（P=0.008;P=0.004）significantly worse than that of normal patients.However,in patients with TNM stage I-II GC cancer,there was no significant difference in OS and DFS compared with normal patients.Univariate Cox regression model analysis showed that histological grade（P=0.040;P=0.039）,preoperative CEA level（P=0.005;P=0.015）,lymph node metastasis（P<0.001;P<0.001）,G6 PD expression level（P=0.017;P=0.016）and PFKFB3 expression level（P=0.009;P=0.005）were one of the prognostic factors of TNM stage III-IV GC patients.However,multivariate Cox regression model analysis indicated that G6 PD and PFKFB3 were not independent prognostic factors in TNM stage III-IV GC patients.By further dividing into subgroups,patients who received XELOX chemotherapy in this stage were selected and performed univariate and multivariate Cox analysis again.It was found that G6 PD and PFKFB3 could be independent prognostic factors in TNM stage III-IV GC patients under XELOX chemotherapy.Conclusion: G6 PD and PFKFB3 are mainly up-regulated in TNM stage III-IV GC patients,and are closely related to the histological grade,preoperative CEA level and lymph node metastasis of human GC tissue.Further studies have shown that the expression of G6 PD and PFKFB3 is related to the prognosis of gastric cancer patients and has the potential ability to predict prognosis.Therefore,G6 PD and PFKFB3 may become prognostic indicators and potential therapeutic targets for gastric cancer patients.