Clinicopathological significance of hypoxia-inducible factor-1 alpha (HIF-1α) expression in gastric cancer

Hypoxia is a common feature of rapidly growing solid tumors. Therefore, cellular adaptation to hypoxia and altered glucose metabolism are fundamental to the biology of cancer cells. Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a transcription factor for more than 60 genes recognized to control the delivery of oxygen and nutrients through the induction of angiogenesis and glycolysis under hypoxic conditions. Therefore, inhibition of the expression of HIF-1 alpha can be expected to be potentially tumor-specific molecular target-based therapy. In this study, we evaluated the significance of HIF-1 alpha expression in relationship to clinicopathological factors, prognosis, vascular endothelial growth factor (VEGF) expression, and microvessel density (MVD). Paraffin-embedded tumor specimens from 128 patients who underwent gastrectomy at Kurume University from 2004 to 2005 were used to assess the clinical significance of HIF-1 alpha expression. We used the ABC method to perform an immunohistochemical analysis of the HIF-1 alpha and VEGF expression. Eighty-four (65.6%) of gastric cancer specimens were positive for HIF-1 alpha expression. Multivariate analysis showed that histology, depth of invasion, VEGF expression, and MVD were significantly associated with HIF-1 alpha expression. On relapse-free and overall survival curves, the HIF-1 alpha-negative group was significantly higher than the HIF-1 alpha-positive group. Moreover, HIF-1 alpha(+)/VEGF(+) patients had the worst prognosis. HIF-1 alpha expression was identified as a significant predictor of relapse-free survival and overall survival by multivariate Cox's proportional hazard analyses. Overexpression of HIF-1 alpha was found to be an indicator of poor prognosis for patients with gastric cancer and was significantly correlated with histology, depth of invasion, VEGF, and MVD.