The expression of hypoxia-inducible factor-1α and its clinical significance in lung cancer: a systematic review and meta-analysis

BACKGROUND: Hypoxia-inducible factor-1 alpha (HIF-1 alpha) plays an important role in tumour progression and metastasis through activation of many target genes that are especially involved in pivotal aspects of cancer biology. However, the prognostic role of HIF-1 alpha has been controversial in primary patients with lung cancer. This meta-analysis was performed to systematically evaluate whether HIF-1 alpha expression is associated with the clinical outcomes in lung cancer patients. METHODS: We retrieved relevant articles from Cochrane library, PubMed, EMbase, CNKI, CBM, VIP and Wan Fang Databases from inception to May 2012. Studies were selected using specific inclusion and exclusion criteria. A systematic review and meta-analysis was performed on the association between HIF-1 alpha expression and clinical outcomes in lung cancer patients. All analyses were performed using the Revman 5.1 software. RESULTS: A total of 30 studies were identified as eligible for the systematic review and meta-analysis. The expression of HIF-1 alpha was significantly higher than those in normal lung tissue; and III-IV stage, lymph node metastasis, poorly differentiation, squamous cell carcinoma and small cell lung cancer (SCLC) were significantly higher than those in I-II stage, no lymph node metastasis, well differentiation, adenocarcinomas and non small cell lung cancer (NSCLC), respectively (odds ratio (OR) = 19.00, 95% confidence interval (CI):12.12-29.78, p<0.00001; OR = 0.23, 95% CI:0.14-0.36, p<0.00001; OR = 3.72, 95% CI:2.38-5.80, p<0.00001; OR = 0.47, 95% CI:0.31-0.70, p<0.00002, OR = 0.24, 95% CI:0.07-0.77, p = 0.02; OR = 0.78, 95% CI:0.63-0.98, p = 0.03). VEGF and CA IX positive expression in HIF-1 alpha positive tumour tissues were significantly higher than those in HIF-1 alpha negative tumour tissues, respectively (OR = 3.23, 95% CI: 1.90-5.46, p<0.0001; OR = 3.84, 95% CI: 2.10-7.03, p<0.0001). The positive HIF-1 alpha tumour tissues of patients had lower 5-year survival rates (OR = 0.13, 95% CI: 0.03-0.47, p = 0.002) and overall survival (relative risk (RR) = 1.68, 95% CI: 1.12-2.50, p = 0.01). CONCLUSIONS: HIF-1 alpha is related to a differing degree of lung cancer cell, lymph node metastasis, post-operative survival time and histology (NSCLC vs. SCLC, adenocarcinomas vs. squamous cell carcinoma). HIF-1 alpha, which combines other proteins, such as vascular endothelial growth factor (VEGF) or CA IX, might serve as important parameters in evaluating biological behaviour and prognosis of lung cancer; it will be of benefit to clinical treatment and prognostic evaluation.