Expression And Significance Of GRHL2,HIF-1α And VEGF In Esophageal Cancer

Objective Esophageal cancer(EC)is a malignant tumor derived from the esophageal epithelium of digestive tract,and it is a serious threat to human health and life which ranks sixth in the global cancer mortality.Although much effort has been made,its5-year survival rates still remains low due to advanced stage at diagnosis,aggressive local invasion,early metastasis and resistance to chemotherapy.Therefore,early diagnosis and treatment is the key to the prevention and control work of EC.EC is a complex and heterogeneous disease,commonly associated with multiple underlying pathogenic mechanisms caused by various risk factors.Therefore,it is of great significance to identify novel and effective molecular markers for EC diagnosis and treatment assessment.Although Grainyhead-like-2(GRHL2)recently has attracted interest for its potential to be identified as a novel suppressor of the epithelialmesenchymal transition(EMT),clinical values of GRHL2 and the relevance with the metastasis related factors,such as hypoxiainducible factor 1α(HIF-1α)and vascular endothelial growth factor(VEGF),remains unclear.In order to clarify the associations between GRHL2,HIF-1α,VEGF and tumor malignant properties and patients prognosis in EC,and to provide new targets for EC targeted therapy,we investigate the expression of GRHL2,HIF-1α and VEGF in both tumor and paracarcinomatous tissues of EC.Meanwhile,we also investigate the relationship between the overexpression of GRHL2,HIF-1α and VEGF and the angiogenesis through counting the microvessels density(MVD)in EC tissues.Methods 63 surgical specimens obtained from patients who were treated in Anhui Provincial Hospital from April,2009 to May,2011 and had complete clinical data were coll ECted.Immunohistochemistry(IHC)was performed for the specimens to detect the levels of GRHL2,HIF-1α and VEGF expression in the EC and paracarcinomatous tissues,and the MVD visibly marked by CD34.The positive rates of GRHL2,HIF-1αand VEGF were calculated by using c2 test.The correlation between the expression of GRHL2,HIF-1α,VEGF and MVD were performed by Spearman’s rank correlation test.The influence of GRHL2,HIF-1α and VEGF expression on patients prognosis was determined by Kaplan-Meier analysis and Log-rank test.The Cox regression model was used for multivariate survival analysis.Results 1.The GRHL2 and VEGF expression in esophageal carcinoma tissues were dramatically higher compared with the paracarcinomatous tissues: the positive rates of GRHL2 and VEGF in the esophageal carcinoma tissues was 85.0%(χ2 =71.85,P=0.000)and 52.4%(χ2 =34.30,P =0.000),respectively.The positive rate of HIF-1α in the EC tissues was 63.5%,which was significantly lower than that in paracarcinomatous tissues(96.8%,χ2 =22.00,P =0.000).2.The levels of HIF-1α and VEGF expression were positively correlated with MVD(HIF-1α: r =0.755,P =0.000;VEGF: r =0.299,P =0.017).3.The positive rate of HIF-1α was closely associated with age greater than or equal to 60(c 2 =6.58,P =0.04),male(c 2 =4.40,P =0.04)and differentiated degree(c2 =4.98,P =0.03);the positive rate of GRHL2 was associated with TNM stage(c 2 =9.50,P =0.01);there was a significant statistical difference between VEGF overexpression and venous invasion(c 2 =6.51,P =0.011).4.The expression of GRHL2 was negatively correlated with HIF-1α(P =0.04),and both disease free survival rates(DFS,P =0.0458)and overall survival rates(OS,P =0.0447)of patients with the low expression of GRHL2 and the high expression of HIF-1αobviously decreased when compared with other patients.5.There was no statistical significance between the levels of GRHL2,HIF-1α and VEGF expression and OS as well as DFS.6.Multivariate survival analysis by the Cox regression model in this study indicated that the GRHL2(P =0.625),HIF-1α(P =0.592)and VEGF(P =0.155)overexpression could not predict patients OS indepen-dently.Conclusion Overexpression of GRHL2 and VEGF are found in esophageal carcinoma tissues.The levels of HIF-1α and VEGF expression are positively correlated with MVD,which can promote angiogenesis of esophageal cancer and provide support for its occurrence and progression.GRHL2 may have a certain antitumor effect in esophageal carcinoma and can impact patients prognosis to an extent.