Expression Of Hypoxia-inducible Factors, Cyclooxygenase-2 In Carcinogenesis Of Esophageal Squamous Cell Cancer And Its Association With Angiogenesis And Clinicopathologic Features

Background: Tumor angiogenesis may play an important role in the process of occurrence and development of esophageal squamous cell cancer (ESCC) including normal esophageal squamous epithelial cell hyperplasia, dysplasia, cancer in situ, early and advanced cancer. Hypoxia-inducible factor-1 alpha and -2alpha (HIF-1α, HIF-2α) are transcription factors induced by hypoxic condition, paly key roles in the pleiotropic response observed under hypoxic conditions. HIF-1α and FflF-2α overexpressed in various cancer tissues and may play critical roles in tumorigenesis and progression by inducing vascular endothelial growth factor (VEGF) to participate in tumor neovascularization. Cyclooxygenase-2 (COX-2), an inducible enzyme that catalyzes the formation of prostaglandins (PGs) from arachidonic acid, is expressed in a variety of human malignant solid tumors, associated with tumor angiogenesis, cell proliferation and inhibition of apoptosis. There maybe complicated synergistic mechanism in carcinogenesis and tumor progression between HIF-1α and COX-2.Aim: To investigate the expression of HIF-1α, HIF-2α, COX-2 and VEGF in the carcinogenesis of ESCC and its relationships of angiogenesis and clinicopathologic features.Methods: In 67 surgically resected specimens from paitents with ESCC, 42 with normal esoghageal mucosa and 40 biopsy specemens from patients with esophageal dysplasia lesions, the expression of HIF-1αmRNA, COX-2mRNA, VEGFmRNA were examined by hybridization in situ and the expression of HIF-1α, HIF-2α, COX-2, VEGF, CD31 protein were examined by immunohistochemical method. We investigated the changes of HIF-1α, HIF-2α, COX-2, VEGF and CD31 expression in three groups, and the correlation of its' expression with MVD and clinicopathologic features was also explored. Results: The expression rate of HIF-1α, HIF-2α, COX-2, VEGF and CD31 in normal esoghageal mucosa, esophageal dysplasia lesions and ESCC respectively were: HIF-1αmRNA ( 16.67%, 35.0%, 65.67% ) ; HIF-1αprotein (0%, 20.0%, 58.21%) ; HIF-2α protein (0%, 7.5%, 29.85% ) ; COX-2mRNA (14.29%, 65.71%, 79.10% ) ; COX-2 protein ( 19.0%, 82.5%, 86.57% ); VEGF mRNA( 26.19%, 34.29%, 62.29% ); VEGF protein (11.9%, 27.5%, 58.21% ) ; MVD (12.71 ±4.571,16.95± 5.486, 33.39±6.688) . In ESCC, HIF-1α, HIF-2α, COX-2, VEGFoverexpression were significantly associated with high MVD, and high HIF-1α expression correlated with COX-2 and VEGF protein expression. HIF-1α, COX-2 and VEGF protein expression correlated with TNM classification, depth of tumour invasion and lymph node metastasis. Conclusions: The expressions of HIF-1α, HIF-2α, COX-2, VEGF and MVD increased as the carcinogenesis of ESCC progressed. HIF-1α, HIF-2α, COX-2 may play important roles in tumorigenesis of ESCC by inducing VEGF expression in tumor angiogenesis. HIF-1α and COX-2 may cooperated each other in ESCC angiogenesis. Overexpression of HIF-1α, COX-2 and VEGF protein could be used as biological markers for evaluating the behavior of ESCC.