Prognostic significance of hypoxia-inducible factor-1α, TWIST1 and Snail expression in resectable non-small cell lung cancer

Background: Metastasis is the most common cause of disease failure and mortality for non-small cell lung cancer (NSCLC) after surgical resection. Snail and TWIST1 are epithelial-mesenchymal transition (EMT) regulators which induce metastasis. Intratumoral hypoxia followed by stabilisation of hypoxia-inducible factor 1 alpha (HIF-1 alpha) promotes metastasis through regulation of certain EMT regulators. The aim of this study was to evaluate the prognostic value of HIF-1 alpha, TWIST1 and Snail expression in patients with resectable NSCLC. Methods: A retrospective analysis of 87 patients with resectable NSCLC from Taipei Veterans General Hospital between 2003 and 2004 was performed using immuno-histochemistry to analyse HIF-1 alpha, TWIST1 and Snail expression. The association between HIF-1 alpha, TWIST1 and Snail expression and patients' overall and recurrence-free survivals was investigated. Results: Overexpression of HIF-1 alpha, TWIST1 or Snail was shown in 32.2%, 36.8% and 55.2% of primary tumours, respectively. Overexpression of HIF-1 alpha, TWIST1 or Snail in primary NSCLCs was associated with a shorter overall survival (p = 0.005, p = 0.026, p = 0.009, respectively), and overexpression of HIF-1 alpha was associated with a shorter recurrence-free survival (p = 0.016). We categorised the patients into four groups according to the positivity of HIF-1 alpha/TWIST1/Snail to investigate the accumulated effects of these markers on survival. Co-expression of more than two markers was an independent prognostic indicator for both recurrence-free survival and overall survival (p = 0.004 and p<0.001, respectively, by multivariate Cox proportional hazards model). Conclusions: Co-expression of more than two markers from HIF-1 alpha, TWIST1 and Snail is a significant prognostic predictor in patients with NSCLC.