Relationship of hypoxia-inducible factor 1alpha and p21WAF1/CIP1 expression to cell apoptosis and clinical outcome in patients with gastric cancer.

Hypoxia-inducible factor-1alpha (HIF-1alpha) plays an essential role in oxygen homeostasis. The expression of HIF-1alpha-inducible genes is associated with tumor progression. p21 mediates cell cycle arrest and is one of the downstream genes targeted by HIF-1. We examined the relationship between HIF-1alpha and p21 expression, apoptosis and tumor progression using tissue specimens obtained surgically from 126 patients with gastric cancer. Immunohistochemical analysis indicated that loss of p21 expression correlated positively with patient age and tumor size. Lymph node metastasis was significantly more frequent in tumors with loss of p21 expression (P = 0.022). HIF-1alpha-positive/p21-negative tumors had a lower apoptotic index than any other tumor samples, and patients with HIF-1alpha-positive/p21-negative tumors also had a significantly poorer prognosis than the other patient populations. These results suggest that loss of HIF-1alpha-dependent p21 expression results in decreased apoptosis, increased cell survival and more aggressive tumors.