Hypoxia‐inducible factor‐1α in non small cell lung cancer: Relation to growth factor, protease and apoptosis pathways

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Abstract
Hypoxia‐inducible factor (HIF)‐1α is the regulatory subunit of HIF‐1 that is stabilized under hypoxic conditions. Under different circumstances, HIF‐1α may promote both tumorigenesis and apoptosis. There is conflicting data on the importance of HIF‐1α as a prognostic factor. This study evaluated HIF‐1α expression in 172 consecutive patients with stage I–IIIA non small cell lung cancer (NSCLC) using standard immunohistochemical techniques. The extent of HIF‐1α nuclear immunostaining was determined using light microscopy and the results were analyzed using the median (5%) as a low cut‐point and 60% as a high positive cut‐point. Using the low cut‐point, positive associations were found with epidermal growth factor receptor (EGFR; p = 0.01), matrix metalloproteinase (MMP)‐9 (p = 0.003), membranous (p < 0.001) and perinuclear (p = 0.004) carbonic anhydrase (CA) IX, p53 (p = 0.008), T‐stage (p = 0.042), tumor necrosis (TN; p < 0.001) and squamous histology (p < 0.001). No significant association was found with Bcl‐2 or either N‐ or overall TMN stage or prognosis. When the high positive cut‐point was used, HIF‐1α was associated with a poor prognosis (p = 0.034). In conclusion, the associations with EGFR, MMP‐9, p53 and CA IX suggest that these factors may either regulate or be regulated by HIF‐1α. The association with TN and squamous‐type histology, which is relatively more necrotic than other NSCLC types, reflects the role of hypoxia in the regulation of HIF‐1α. The prognostic data may reflect a change in the behavior of HIF‐1α in increasingly hypoxic environments.

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