Hypoxia-inducible factor (HIF) in human tumorigenesis.

Hypoxia is a major event that occurs in most solid tumors. Intratumoral hypoxia is sufficient to activate the key transcription factor, hypoxia-inducible factor (HIF) that mediates the activation of the "survival machinery" in cancer cells. HIF can also be induced by oxygen-independent genetic alterations that activate a variety of oncogenic signaling pathways or inactivate tumor suppressors. Increased tumor HIF occurs at early stages of carcinogenesis and is often correlated with increased angiogenesis, malignant progression, poor patient prognosis and chemoradio-resistance. HIF-alpha subunit, the oxygen-regulated subunit of HIF is overexpressed in a wide range of human solid tumors. Nuclear HIF-alpha protein immunostaining was restricted to tumor cells compared to normal tissues. Herein, we review and discuss the role of HIF in tumorigenesis and describe the overexpression of HIF-alpha proteins in human cancers and its association with overall clinical outcomes.