Hypoxia-inducible Factor-1 Alpha, in Association with TWIST2 and SNIP1, is a Critical Prognostic Factor in Patients with Tongue Squamous Cell Carcinoma

It has become apparent that hypoxia and hypoxia-inducible factor-1 (HIF-1) activation have the potential of modulating the activity of major epithelial-mesenchymal transition (EMT)-triggering pathways by regulating the expression and activity levels of major transcriptional repressors. The aim of our study was to elucidate the role of HIF-1α and HIF-2α, and EMT regulators TWIST2 and SMAD nuclear interacting protein-1 (SNIP1) in tongue squamous cell carcinoma (TSCC). A retrospective analysis of 89 patients with TSCC from Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University between 2002 and 2005 was performed using immunohistochemistry in paraffin-embedded and formalin-fixed tissues to analyze HIF-1α, HIF-2α, TWIST2 and SNIP1 expression. The association between HIF-1α, HIF-2α, TWIST2 and SNIP1 expression and patient survivals was investigated. Our results showed that overexpression of HIF-1α, HIF-2α, TWIST2 and SNIP1 were shown in 49.44% (44/89), 55.06% (49/89), 44.94% (40/89) and 34.83% (31/89) of TSCC, respectively. Overexpression of HIF-1α, TWIST2 and SNIP1 in TSCC was associated with a shorter disease-free survival (P=0.003, P=0.001, P=0.040, respectively), and HIF-2α had no significant association with either overall survival (P=0.195) or disease-free survival (P=0.356). Co-expression of more than two markers of HIF-1α, TWIST2 and SNIP1 was an independent prognostic indicator for both overall survival and disease-free survival by multivariate Cox proportional hazards model. It is proposed that co-expression of more than two markers from HIF-1α, TWIST2 and SNIP1 might be a significant prognostic predictor in patients with TSCC.