Prognostic value of HIFs expression in head and neck cancer: a systematic review

PLoS One. 2013 Sep 13;8(9):e75094. doi: 10.1371/journal.pone.0075094. eCollection 2013.

Abstract

Background: Tumor hypoxia plays a fundamental role in resistance to therapy and disease progression. A number of studies have assessed the prognostic role of HIFs expression in head and neck cancer (HNC), but no consistent outcomes are reported.

Methodology: A systematical search was performed to search relevant literatures in PubMed, Web of Science and ISI Web of Knowledge databases. The patients' clinical characteristics and survival outcome were extracted. The correlation between HIFs expression and prognosis was analyzed.

Principal findings: A total of 28 studies assessed the association between HIFs and HNC survival, the result showed that overexpressed HIFs was significantly associated with increase of mortality risk (HR = 2.12; 95% CI: 1.52-2.94; I(2) 74%). Subgroup analysis on different HIF isoforms with OS indicated that both HIF-1α and HIF-2α were associated with worse prognosis. The pooled HRs were 1.72(95% CI 1.34-2.20; I(2) 70.7%) and 1.79(95% CI: 1.42-2.27, I(2) 0%). Further subgroup analysis was performed by different geographical locations, disease subtype, stage, types of variate analysis and cut-off value. The results revealed that overexpressed HIF-1α was significantly associated with poor prognosis in Asian patients (HR = 2.34; 95% CI: 1.76-3.1; I(2) 48.9%), but not in European patients (HR = 1.13; 95% CI: 0.77-1.66; I(2) 78.3%). Furthermore, HIF-1α overexpression was significantly associated with worse OS in oral carcinoma (HR = 2.1; 95% CI: 1.11-3.97; I(2) 81.7%), nasopharyngeal carcinoma (HR = 2.07; 95% CI:1.23-3.49; I(2) 22.5%) and oropharynx carcinoma (HR = 1.76; 95% CI:1.05-2.97; I(2) 61%), but not in laryngeal carcinoma (HR = 1.38; 95% CI: 0.87-2.19; I(2) 62.5%). We also found that the prognostic value of HIF-1α overexpression existed only when using staining and percentage as positive definition (HR = 1.82; 95% CI 1.42-2.33; I(2) 9.9%).

Conclusions: This study showed that overexpressed HIFs were significantly associated with increase of mortality risk. Subgroup analysis revealed that overexpressed HIF-1α was significantly associated with worse prognosis of HNC in Asian countries. Additionally, HIF-1α had different prognostic value in different HNC disease subtypes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Asia
  • Basic Helix-Loop-Helix Transcription Factors / biosynthesis
  • Disease-Free Survival
  • Europe
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis*
  • Mouth Neoplasms / metabolism*
  • Mouth Neoplasms / mortality*
  • Oropharyngeal Neoplasms / metabolism*
  • Oropharyngeal Neoplasms / mortality*
  • Survival Rate

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • endothelial PAS domain-containing protein 1

Grants and funding

This work was supported by the Nature science foundation of Zhejiang Province (Grant No. LY12H13002), project of Zhejiang Traditional Chinese Medicine Administration (Grant No.2012ZZ012), project of Zhejiang medical health science plan (Grant No.2011KYA145), project of Zhejiang traditional Chinese medicine research (Grant No. 2013ZB115) and Nature science foundation of Ningbo City (Grant No 2012A610205, 2012A610206). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.