Study On Relationship Of ING4, VEGF Expression And Esophageal Squamous Cancer Generation, Development And Prognosis

Objective: Derived from esophageal squamous epithelial tissue,accounting for2%of all malignant tumors, esophageal cancer is the mostcommon malignancy in the world. At present, China is the country which hasone of the highest esophageal cancer mortality in the world, with annualfatality of15.59/100,000. In recent years, the number of esophageal cancerpatients has increased significantly, as a serious hazard for people's health.Most preliminary diagnosed patients are already at the intermediate or latestage, for which the treatments are surgical and chemotherapy treatment bothincluding palliative surgery and radical surgery. The surgical treatment gives alow survival rate. Therefore, the research into esophageal squamous cancergeneration, development and prognosis from the prospective of molecular hasbecome the key of the esophageal cancer study.From the perspective of molecular, malignant tumors can be regarded asa genetic disease, caused by gene mutation due to certain chromosomal DNAdamage, which leads to uncontrolled growth of cells, the lack ofdifferentiation and thus abnormal proliferation, further invasion into thenormal tissues and organs and eventually spread to the whole body. Thegeneration, development, invasion and metastasis of malignant tumors areclosely correlated with the expression level of multiple genes and molecular.Inhibitor of growth family(ING) is an important group of tumor suppressor,including five members: INGl, ING2, ING3, ING4and ING5. The five genesencodes seven kinds of protection, including3kinds of products of INGl gene(INGla, INGlb and INGlc) and encoding proteins of the other four members ofthe ING gene family. ING4(inhibitor of growth family member4) gene,discovered by Shiseki M and others in2003, is a new member of the family of tumor suppressor genes ING. This gene is a tumor suppressor gene recentlydiscovered. ING4plays an important role in participation in the regulation ofp53gene activity, inhibition of the proliferation of the tumor vessels,inhibition of cell adaptation to hypoxia, the loss of cell contact inhibition andthe sensitivity of cells to chemical drugs as well as many other aspects thatinfluence the tumor generation, development and treatment. Vascularendothelial growth factor (VEGF) belongs to platelet-de-rived growth factor(PDGF) family, which is of a dimeric cysteine superfamily of growth factors.VEGF is the most important angiogenic growth factor which can be combinedwith the vascular endothelial cell specificity, stimulating the endothelial cellgrowth, inducing angiogenesis, maintaining the tumor growth, and thusresulting in cell proliferation of tumours. At present, there are few reports onING4and VEGF expression in esophageal squamous cell carcinoma (ESCC).In our study, we have collected the VEGF and ING4impression in112paraffin blocks of ESCC, removed from January to July2005, from thoracicsurgery department in the Fourth Hospital of Hebei Medical University,analyzed the relationship between VEGF and ING4expression and esophagealcancer clinicopathological parameters, thus analyzing the relationship betweenING4and VEGF expression, and combined with clinical follow-up data,analyzed its relationship with esophageal cancer prognosis.Methods:We have used immunohistochemistry method to analyze ING4and VEGF expression products in the tissue of esophageal squamous cellcarcinoma patients of the different stages, so as to analyze the relationbetween ING4and VEGF, and Kaplan-Meier life table method has beenadopted to analyze its relationship with prognosis. The samples were collectedfrom112paraffin blocks of ESCC between January to July2005from thethoracic surgery department in the Fourth Hospital of Hebei MedicalUniversity. And35normal paraneoplastic tissues (more than5cm from cancertumor tissues) were collected as the normal control group. Of the112esophageal squamous cell carcinoma, there are77males and35females, agedfrom32to76, with the median age of56. Collection criteria: radical excision, with complete clinical data and post-operative follow-up, and nochemotherapy or radiotherapy received before surgery. All samples were fixedin formalin, embedded in paraffin, bladed in5um serial sections, treated withHE and immunohistochemical staining respectively, with PBS as the negativecontrol, and only secondary antibody as the positive control.We have used SPSS.13.0software to analyze all the experimental data,Chi-square test for the enumeration data, the Spearman rank correlationanalysis for between two variables, the Kaplan-Meier method for thecalculation of survival rate, thus describing the survival curve, the Log-ranktest for analysis of the survival rate difference,and the Cox proportionalhazards regression model for multivariate analysis. P <0.05indicates astatistical difference,(P <0.01) indicates a significant difference (Test standard:a=0.05).Results:1ING4positive expression rate in ESCC tissues is53.6%(60/112), whilethe positive expression in adjacent normal esophageal tissues is87.5%(30/35). It has indicated statistical significant (P<0.01).2ING4expression is uncorrelated with patients' age, sex, lymphoid nodemetastasis and depth of invasion (P>0.05), and correlated with the degreeof differentiation and prognosis of ESCC (P<0.05).3VEGF positive expression rate in ESCC tissues is78.6%(88/112), whilethe positive expression in adjacent normal esophageal tissues is20.0%(7/35). It has indicated statistical significant (P<0.01).4VEGF expression is uncorrelated with patients' age, sex, lymphoid nodemetastasis and depth of invasion (P>0.05), and correlated with the degreeof differentiation and prognosis of ESCC (P<0.05).5ING4expression in ESCC has a negative correlation with VEGFexpression (r=-0.284, P=0.002, P <0.01). Cox proportional hazardsregression models show that the depth of invasion, ING4and VEGF are allimportant prognostic factors influencing prognosis.Conclusions: 1ING4positive expression rate in ESCC tissues is significantly lower thanin adjacent normal tissues, indicating that the low ING4expression may beclosely correlated with the occurrence of ESCC.2Those with high ING4expression in ESCC tissues have good prognosis.3VEGF positive expression rate in ESCC tissues is significantly higher thanin adjacent normal tissues, indicating that high VEGF expression may beclosely correlated with the occurrence of ESCC.4Those with high VEGF expression in ESCC tissues have poor prognosis.5ING4expression and VEGF expression in ESCC are negatively correlated.6ING4and VEGF are probably independent factors influencing prognosisof ESCC patients and are of certain value in judging the prognosis ofpatients.