Clinical and prognostic significance of HIF-1α, PTEN, CD44v6, and survivin for gastric cancer: a meta-analysis

PLoS One. 2014 Mar 19;9(3):e91842. doi: 10.1371/journal.pone.0091842. eCollection 2014.

Abstract

Purpose: This study was to quantitatively summarize published data for evaluating the clinical and prognostic significance of four proteins involved in hypoxia-inducible factor-1 (HIF-1α) regulation of the metastasis cascade.

Methods: Searches were performed using the MEDLINE, EMBASE, Cochrane Library, and Chinese Biomedicine databases without any language restrictions. Studies were pooled and either the summary risk ratio (RR) or odds ratio (OR) was calculated. Potential sources of heterogeneity were sought out via subgroup and sensitivity analyses, and publication bias was also performed.

Results: Seventeen studies evaluated HIF-1α, 20 studies evaluated phosphatase and tensin homolog (PTEN), 20 studies evaluated Survivin, and 16 studies evaluated CD44v6. Our results showed that increased HIF-1α expression was linked to a poor 5-year overall survival (RR = 1.508; 95% confidence interval (CI) 1.318-1.725; P<0.001). Decreased survival was heavily influenced by advanced tumor invasion (OR = 3.050; 95% CI 2.067-4.501; P<0.001), lymph node metastasis (1415 patients; OR = 3.486, 95% CI 2.737-4.440; P<0.001), distant metastasis (OR = 6.635; 95% CI 1.855-23.738; P = 0.004), vascular invasion (OR = 2.368; 95% CI 1.725-3.252; P<0.001), dedifferentiation (OR = 2.112; 95% CI 1.410-3.163; P<0.001), tumor size (OR = 1.921; 95% CI 1.395-2.647; P<0.001), and a higher TNM stage (OR = 2.762; 95% CI 1.941-3.942; P<0.001). Similarly, aberrant expression of PTEN, CD44v6, and Survivin were also observed in tumors that correlated with poor OS. The higher ORs of death at 5 years were 1.637 (95% CI = 1.452-1.845; P<0.001), 1.901 (95% CI = 1.432-2.525; P<0.001), and 1.627 (95% CI = 1.384-1.913; P<0.001), respectively, with an OR>2 for the main stratified meta-analyses of clinical factors.

Conclusions: Our findings indicate that HIF-1α/PTEN/CD44v6/Survivin, as measured by immunohistochemistry, can be used to predict the prognosis and potential for invasion and metastasis in Asian patients with gastric cancer. The development of strategies against this subset of proteins could lead to new therapeutic approaches.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Hypoxia
  • Female
  • Humans
  • Hyaluronan Receptors / metabolism*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Inhibitor of Apoptosis Proteins / metabolism*
  • Male
  • Middle Aged
  • Models, Biological
  • Neoplasm Metastasis
  • PTEN Phosphohydrolase / metabolism*
  • Prognosis
  • Publication Bias
  • Stomach Neoplasms / metabolism*
  • Stomach Neoplasms / pathology
  • Survival Analysis
  • Survivin

Substances

  • BIRC5 protein, human
  • CD44v6 antigen
  • HIF1A protein, human
  • Hyaluronan Receptors
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Inhibitor of Apoptosis Proteins
  • Survivin
  • PTEN Phosphohydrolase
  • PTEN protein, human

Grants and funding

This work is supported by the grants from National Natural Science Foundation of China (81260339 and 81301886) and Fundamental Research Funds for Ningxia Medical University (XT2012009 and XQ2012014). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.