Dysregulation of hypoxia inducible factor-1alpha in head and neck squamous cell carcinoma cell lines correlates with invasive potential

Noam A Cohen, Stephen Y Lai, Amy F Ziober, Barry L Ziober
Laryngoscope 2004, 114 (3): 418-23

OBJECTIVES/HYPOTHESIS: Tumor hypoxia appears to be closely associated with tumor propagation, malignant progression, and resistance to radiotherapy. Hypoxia inducible factor-1alpha (HIF-1alpha) is a transcription factor that is upregulated under hypoxic conditions and activates hypoxic adaptation pathways which include neovascularization, erythropoiesis, and glycolysis. Hypoxia inducible factor-1alpha is under tight regulation with undetectable levels of expression in normoxia and robust expression in hypoxia. Mutations that activate oncogenes or inactivate tumor suppressor genes increase the expression of HIF-1alpha. Furthermore, it has been demonstrated that HIF-1alpha is overexpressed in head and neck squamous cell carcinoma and that the degree of expression has predictive and prognostic significance for patients undergoing radiotherapy. The study investigated whether overexpression of HIF-1alpha in head and neck squamous cell carcinoma results from a physiological response to local hypoxia or from oncogenic mutational progression.

STUDY DESIGN: Expression of HIF-1alpha under normoxic and hypoxic conditions was evaluated in cell lines derived from head and neck squamous cell carcinoma. Cell lines that were used displayed varying degrees of in vitro invasiveness.

METHODS: Hypoxia inducible factor-1alpha expression was detected by Western blot analysis. Cells were treated for 3 hours in 1% oxygen, then re-exposed to normoxia for varying times before lysis and detection of HIF-1alpha.

RESULTS: Under normoxic conditions, HIF-1alpha expression was upregulated in invasive cells compared with noninvasive cells, and the degradation of HIF-1alpha following a hypoxic stimulus was blunted in invasive cells as compared with noninvasive cells.

CONCLUSION: The authors presented evidence that dysregulation of HIF-1alpha may play a role in the malignant progression of head and neck squamous cell carcinoma. It is likely that dysregulated expression of the transcription factor HIF-1alpha contributes to the invasive properties associated with hypoxia and advanced head and neck squamous cell carcinoma.

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