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

Jung-Jyh Hung ^1*, Muh-Hwa Yang ¹, Han-Shui Hsu ¹, Wen-Hu Hsu ¹ and Kou-Juey Wu ²

¹ Taipei Veterans General Hospital, Taiwan
² National Yang-Ming University, Taiwan

^* To whom correspondence should be addressed. E-mail: bradley.hung{at}gmail.com.

Accepted 8 September 2009

Abstract

Objective: Metastasis is the most common cause of disease failure and mortality for non-small cell lung cancer (NSCLC) after surgical resection. Both Snail and TWIST1 are epithelial-mesenchymal transition (EMT) regulators which induce metastasis. Intratumoral hypoxia followed by stabilization of hypoxia-inducible factor-1 (HIF-1) promotes metastasis through regulation of certain EMT regulators. The aim of this study is to evaluate the prognostic value of HIF-1, TWIST1 and Snail expression in resectable NSCLC patients.

Methods: A retrospective analysis of 87 patients with resectable NSCLC from Taipei Veterans General Hospital between 2003 and 2004 was performed using immunohistochemistry to analyze HIF-1, TWIST1 and Snail expression. The association between HIF-1, TWIST1 and Snail expression and patients' overall and recurrence-free survivals was investigated.

Results: Overexpression of HIF-1, TWIST1 or Snail was shown in 32.2%, 36.8% and 55.2% of primary tumors, respectively. Overexpression of HIF-1, TWIST1 or Snail in primary NSCLCs was associated with a shorter overall survival (P = 0.005, 0.026, 0.009, respectively), and overexpression of HIF-1 was associated with a shorter recurrence-free survival (P = 0.016). We categorized the patients into four groups according to the positivity of HIF-1/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 < 0.001, respectively, by multivariate Cox proportional hazards model).

Conclusions: Co-expression of more than two markers from HIF-1, TWIST1 and Snail is a significant prognostic predictor in NSCLC patients.