Expression of Hypoxia-inducible Factor-1alpha in Esophageal Squamous Cell Carcinoma: Relationship to Prognosis and Tumor Biomarkers

Yang, Il Jong; Cho, Sung Rae; Kim, Jong In; Lee, Hae Young; Chun, Bong Kwon

Abstract

BACKGROUND
Tissue hypoxia is a characteristic of many human malignant neoplasms, and hypoxia inducible factor-1 (HIF-1) plays a pivotal role in essential adaptive response to hypoxia, and activates a signal pathway for the expression of the hypoxia-regulated genes, resulting in increased oxygen delivery or facilitating metabolic adaptation to hypoxia. Increased level of HIF-1alpha has been reported in many human malignancies, but in esophageal squamous cell carcinoma, the influence of HIF-1alpha on tumor biology, including neovascularization, is not still defined. MATERIAL AND METHOD: The influence of HIF-1alpha expression on angiogenic factors, correlation between the tumor proliferation and HIF-1alpha expression, interaction of HIF-1alpha expression and p53, and correlation between HIF-1alpha expression and clinicopathological prognostic parameters were investigated, using immunohistochemical stains for HIF-1alpha, VEGF, CD34, p53, and Ki-67 on 77 cases of resected esophageal squamous cell carcinoma. RESULT: HIF-1alpha expression in cancer cells was found in 33 of 77 esophageal squamous cell carcinoma cases. The 33 cases (42.9%) showed positive stain for HIF-1alpha. High HIF-1alpha expression was significantly associated with several pathological parameters, such as histologic grade (p=0.032), pathological TMN stage (p=0.002), the depth of tumor invasion (p=0.022), regional lymph node metastasis (p=0.002), distant metastasis (p=0.049), and lymphatic invasion (p=0.004). High HIF-1alpha expression had significant VEGF immunoreactivity (p=0.008) and Ki-67 labeling index (p<0.001), but was not correlated with microvascular density within tumors (p=0.088). The high HIF-1alpha expression was correlated with aberrant p53 accumulation with a marginal significance (p=0.056). The overall 5-year survival rate was 34.9%. The survival rate of patients with a high HIF-1alpha expression was worse than that of patients with low-expression tumors (log-rank test, p=0.0001). High HIF-1alpha expression was independent unfavorable factors although statistical significance is marginal in multivariate analysis.
CONCLUSION
It is suggested that (1) high HIF-1alpha expression in esophageal squamous cell carcinoma is associated with tumor hypoxia, or with genetic alteration in early carcinogenesis and progressive stages, (2) high HIF-1alpha expression may be associated with intratumoral neovascularization through HIF-VEGF pathway, and (3) high HIF-1alpha expression is associated with poor prognosis in patients with esophageal squamous cell carcinoma and may play a role as biomarker for regional lymph node metastasis.