Expression of Hypoxia-inducible Factor-1alpha in Non-small Cell Lung Cancer: Relationship to Prognosis and Tumor Biomarkers

Cho, Sung Rae; Byun, Joung Hun; Kim, Jong In; Lee, Bong Geun; Chun, Bong Kwon

Abstract

BACKGROUND: Tissue hypoxia is characteristic of many human malignant neoplasm, 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 increasing O2 delivery or facilitating metabolic adaptation to hypoxia. Increased level of HIF-1alpha has been reported in many human malignancies, but in non-small cell lung carcinoma the influence of HIF-1alpha on tumor biology, including neovascularization, is not still defined. In present study the relationship of HIF-1alpha expression on angiogenetic factors, relationship between the tumor proliferation and HIF-1alpha expression, interaction of HIF-1alpha expression and p53, and relationship between HIF-1alpha expression and clinico-pathological prognostic parameters were investigated. MATERIAL AND METHOD: Archival tissue blocks recruited in this study were retrieved from fifty-nine patients with primary non-small cell lung carcinoma, who underwent pneumonectomy or lobectomy from 1997 to 1999. HIF-1alpha, VEGF (vascular endothelial growth factor), and p53 protein expression and Ki-67 labeling index in tumor tissues were evaluated, using a standard avidin-biotin-peroxidase complex (ABC) immunohistochemistry. Relationship between the HIF-1alpha expression and VEGF, p53 overexpression and correlation between the HIF-1alpha expresseion and Ki-67 index were analyzed. Clinico-pathologic prognostic parameters were also analyzed. RESULT: HIF-1alpha expression in cancer cells was found in 24 of 59 cases of non-small cell lung carcinoma (40.7%). High HIF-1alpha expression was significantly associated with several pathological parameters, such as pathological TMN stage (p=0.004), pT stage (p=0.020), pN stage (p=0.029), and lymphovascular invasion (p=0.019). High HIF-1alpha expression was also significantly associated with VEGF immunoreactivity (p<0.001), and aberrant p53 expression (p=0.040). but was marginally associated with Ki-67 labeling index (p=0.092). The overall 5-year survival rate was 42.3%. The survival curve of patients with a high HIF-1alpha expression was worse than that of patients with low-expression (p=0.002). High HIF-1alpha expression was independent unfavorable factors with a marginal significance in multivariate analysis performed by Cox regression.
CONCLUSION
It is suggested that high HIF-1alpha expression may be associated with intratumoral neovascularization possibly through HIF-VEGF pathway, and high HIF-1alpha expression could be associated with lymph node metastasis and post operative poor prognosis in patients with non-small cell lung ca