Expression Of EphB4 And HIF-1α And Their Influence On Angiogenesis In Human Gastric Carcinoma

Stomach carcinoma is one of the most common cancers in China.The patients' poorly prognosis is mainly caused by aggression and metastasis of gastric cancer.So further investigation into the mechanisms of invasion and metastasis of gastric cancer would help to prolong overal survival and to improve the prognosis.The studies have confirmed that angiogenesis is persistent and uncontrollable in the development and progression of human cancers.Not only do new blood vessels contribute to growth of cancer,but also promote invasion and metastasis,affecting biological behaviors of tumors,Intratumor microvessel density(MVD)is a quantitative measure of angiogenesis and a independent prognostic factor for various malignant tumors.Recently it was shown that Erythropoietin-Producing Hepatocellular B4 Receptor(EPHB4 receptor)and its ligand had an important role in tumor pathological angiogenesis.And Hypoxia Inducible Factor-1(HIF-1)promoted growth of cancer and metastasis through transcription of target gene involving many biological effects,including angiogenesis.It have been reported that hypoxia induced up-regulation of HIF-1αand EphB4 and HIF-1αwas an important regulatory factor for EphB4 expression in tissue repair and wound healing.Howerer,to the best of our knowledge,the coexpression of EphB4 and HIF-1αand their role in angiogenesis in stomach cancer remains unclear.This study is to investigate the expressions of EphB4 receptor and HIF-1αprotein in human primary gastric carcinoma,to analyze their correlation with angiogenesis,and to explore association between EphB4 and HIF-1αfurther.In this study the expressions of EphB4 receptor,HIF-1αprotein and CD34 were detected in 74 human primary gastric carcinoma specimens(gastric carcinoma group)and in 13 normal gatric mucosa tissues(control group)by immunohistochemistry.Intratumor microvessel density(MVD)was measured according to the result of CD34 protein staining.Correlations between proteins expression and clinicalpathological factors were analyzed by statistics.Analysis of relationship between proteins expression and MVD,as well as association between EphB4 and HIF-1α,was performed alike.The results showed that percentage of overexpressions of EphB4 receptor and HIF-1αprotein were 62.16%(46/74)and 52.7%(39/74)in gastric carcinoma group,respectively,while EphB4 receptor and HIF-1αprotein overexpressed in 15.38%(2/13)and 0%(0/13)of control group,respectively.EphB4 receptor and HIF-1αprotein expressed significantly higher in gastric carcinoma group than in normal control group(P＜0.01).In gastric carcinoma group,the expressions of EphB4 receptor and HIF-1αprotein were closely related to histologic classification,histologic grade and clinicopathological stage of gastric carcinoma (P＜0.05).The expression of EphB4 receptor was also relevant to the depth of gastric carcinoma invasion(P＜0.05),while HIF-1αprotein had no correlation with it.MVD was 51.735±18.576 in gastric carcinoma group and significantly higher than that in control group(28.062±11.585;P＜0.01).In gastric tumor,close correlation was found between MVD and histologic classification,histologic grade,depth of invasion and p-TNM stage(P＜0.05).And MVD were observed in significantly higher levels in tumors with EphB4 receptor and HIF-1αprotein overexpressed(61.835±13.908,59.621±17.578,respectively)than in tumors with low EphB4 receptor and HIF-1αprotein expression(35.143±12.299 and 42.949±15.643,respectively;P＜0.01).In stomach cancer group,26 specimens coexpressed EphB4 receptor and HIF-1αprotein(35.13%),significantly higher than in control group(P＜0.05).In addition,a significant positive correlation was observed between EphB4 receptor and HIF-1αprotein expression(P＜0.01,r =0.2091).In Conclusion,these data reveals that EphB4 receptor and HIF-1αprotein overexpression be significantly correlated with tumorigenesis and malignant biological behavior of gastric cancer.Overexpressions of EphB4 receptor and HIF-1αprotein contribute to aggression and metastasis of stomach carcinoma. Angiogenesis is significant in gastric tumor progression.The overexpressions of EphB4 receptor and HIF-1αprotein play an importmant role in the tumor angiogenesis in gastric carcinoma.HIF-1αis an important regulatory factor for EphB4 in stomach cancer.HIF-1αup-regulates the expression of EphB4 receptor, promotes angiogenesis and contributes to aggression and metastasis of stomach carcinoma.