The Clinical And Experimental Investigation Of Correlation Between CXCR4 And MMP-9, VEGF Expressions In Esophageal Cancer

BACKGROUNDEsophageal cancer is a common disease of alimentary tract. The standard treatment is multimodality therapy, which is combined surgery with chemotherapy and radiotherapy. However, the trauma due to operation and the adverse effects of adjuvant treament restrict the development of multimodality therapy. To investigate the mechanism of invasion, metastasis and then find out the molecular target have become the new focus in the treatment of esophageal cancer. In recent years, CXCR4 was found to be expressed in many tumors and significantly correlated with invasion, angiogenesis, metastasis and prognosis. MMP-9 and VEGF were the important fators in tumor invasion and angiogenesis, respectively. In this study, we will investigate the expressions of CXCR4, MMP-9 and VEGF in esophageal squamous cell cancer and analyze their associations with patients's clinicopathological features and prognosis.METHODSWe collected the paraffin-embedded samples, as well as medical records and follow-up data of 127 patients with esophageal cancer, who were treated by thoracic surgery in Zhongshan Hospital in 2005. The CXCR4, MMP-9 and VEGF expressions in esophageal cancer tissues were evaluated according to the immunohistochemical staining area and intensity. The associations between patients' prognosis and covariates were analyzed by Kaplan-Meier method (univariate analysis) and Cox regression (multivariate analysis).RESULTSThe overall expression rate of CXCR4, MMP-9 and VEGF was 88.2%, 93.7% and 79.5%, respectively. CXCR4 expression was significantly associated with tumor grade, tumor size, tumor depth, regional lymph node metastasis and TNM stage (P<0.05). MMP-9 expression was significantly associated with age and tumor grade (P<0.05). VEGF expression was significantly associated with tumor grade, tumor depth and TNM stage (P<0.05). CXCR4 expression was positively correlated with MMP-9 expression (P<0.01, r =0.365) and VEGF expression (P<0.01, r=0.380). However, there was no significant association between MMP-9 and VEGF expressions (P>0.05). In univariate analysis, CXCR4 expression, tumor size, tumor depth, regional lymph node metastasis and TNM stage were correlated with patients' prognosis (P<0.05); in multivariate analysis, tumor size and regional lymph node metastasis were the independent factors of poor prognosis.CONCULSIONSCXCR4 was highly expressed in esophageal cancer and correlated with MMP-9, VEGF, clinicopathological features and prognosis. We speculated CXCR4 play an important role during the progression of this disease and CXCR4 might participate in the regulation of MMP-9 and VEGF secretions. BACKGROUNDTargeted thearpy has become the focus of cancer research with the development of molecular biology. As a typical targeted drug, the small-molecule tyrosine kinase inhibitors (Gefitinib, Erlotinib) have been approved for clinical treatment of no small cell lung cancer and got the promising effect. However, there was no effective targeted drug used in clinical treatment for esophageal caner. Through the previous study of Part 1, we found that CXCR4 was highly expressed in esophageal cancer and significantly associated with patients' clinicopathological features, prognosis and MMP-9, VEGF expressions. The aim of this study was to investigate the influence of CXCR4 downregulation on proliferation, apopotosis, invasion and MMP-9, VEGF expressions in Eca109 cell line in vitro.METHODSFour RNA interference sequences targeted for CXCR4 were constructed and transfected into Eca109 cell with the vector of plasmid. The best effective RNA interference plasmid was selected by Real time PCR and Western blot. After downregulating the expression of CXCR4 in Eca109 cell by the best effective plasmid transfection, the cell proliferation, apoptosis, invasion and the expressions of MMP-9 and VEGF were detected by MTT assay, flow cytometry, transwell assay and Western blot, respectively.RESULTSNumber 2 plasmid showed the best RNA interference effect according to the detection of Real time PCR and Western blot. And then, Eca109 was transfected with Number 2 plasmid for the experiments. Compared with the negative control (no plasmid transfection) and the nonspecific control, the invasion ability of Eca109 cell transfected with RNA interference plasmid was significantly lower (P<0.05), as well as the expressions of MMP-9 and VEGF (P<0.01). However, no difference was foundin cell proliferation or apoptosis (P>0.05).CONCULTIONSMMP-9,VEGF expressions were regulated by CXCR4, which would act as an important role in Eca109 cell's invasion and angiogenesis; CXCR4 might be a novel therapeutic target of esophageal cancer in the future.