HIF-1 modulates head and neck cancer progression and invasion

Abstract

Problem: Head and neck squamous cell carcinoma (HNSCC) cells rapidly expend oxygen and nutrients supplied by local vasculature. Although hypoxia and hypoglycemia may inhibit new cell division or increase cell death, those tumor cells most capable of adaptation to these conditions may have a selective advantage leading to greater malignant behavior. Adaptive mechanisms, such as angiogenesis and glycolysis, are mediated by hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor. We tested the hypothesis that HIF-1 expression in HNSCC modulates tumor progression and invasion. Methods: We examined the expression of HIF-1alpha in 6 representative HNSCC cell lines under normal and hypoxic (1% O2) conditions. In a Matrigel invasion assay, we compared the invasive characteristics of cell lines derived from metastatic tumor sites (eg, UM-SCC-22B) and those derived from primary tumor specimens (eg, UM-SCC-22A) under normal and hypoxic conditions. We also assessed the effects of a constitutively active HIF-1 mutant stably expressed within HNSCC cell lines. Results: All HNSCC cell lines tests demonstrated robust stimulation of HIF-1alpha on exposure to hypoxic conditions (1% O2). UM-SCC-22B cells expressed increased HIF-1alpha under normal oxygen levels as compared to UM-SCC-22A cells. UM-SCC-22B cells also displayed increased invasion as compared to UM-SCC-22A cells. Invasion was increased in both UM-SCC-22A and UM-SCC-22B cells under hypoxic conditions. Expression of a constitutively active HIF-1alpha mutant increased Matrigel invasion of the UM-SCC-22A and UM-SCC-22B cells in normoxic conditions. Conclusion: HIF-1alpha expression is increased in HNSCC cells under hypoxic conditions and appears to be enhanced in HNSCC cell lines derived from metastatic tumor sites. HNSCC cell lines display increased invasion under hypoxia and with the expression of a constitutively active HIF-1alpha mutant. Significance: Therapeutic interventions targeting HIF-1alpha may be effective in altering HNSCC progression and invasion. Support: None reported.