The A Allele at rs13419896 of EPAS1 Is Associated with Enhanced Expression and Poor Prognosis for Non-Small Cell Lung Cancer

PLoS One. 2015 Aug 11;10(8):e0134496. doi: 10.1371/journal.pone.0134496. eCollection 2015.

Abstract

Hypoxia-inducible factor-2α (HIF-2α, or EPAS1) is important for cancer progression, and is a putative biomarker for poor prognosis for non-small cell lung cancer (NSCLC). However, molecular mechanisms underlying the EPAS1 overexpression are not still fully understood. We explored a role of a single nucleotide polymorphism (SNP), rs13419896 located within intron 1 of the EPAS1 gene in regulation of its expression. Bioinformatic analyses suggested that a region including the rs13419896 SNP plays a role in regulation of the EPAS1 gene expression and the SNP alters the binding activity of transcription factors. In vitro analyses demonstrated that a fragment containing the SNP locus function as a regulatory region and that a fragment with A allele showed higher transactivation activity than one with G, especially in the presence of overexpressed c-Fos or c-Jun. Moreover, NSCLC patients with the A allele showed poorer prognosis than those with G at the SNP even after adjustment with various variables. In conclusion, the genetic polymorphism of the EPAS1 gene may lead to variation of its gene expression levels to drive progression of the cancer and serve as a prognostic marker for NSCLC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alleles*
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / mortality*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Female
  • Gene Expression*
  • Gene Frequency
  • Genes, Reporter
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / mortality*
  • Lung Neoplasms / pathology
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Polymorphism, Single Nucleotide*
  • Prognosis
  • Survival Analysis

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • endothelial PAS domain-containing protein 1

Grants and funding

This work was partly supported by Grant-in-Aid for Scientific Research (C) (No. 23592766) from Japan Society for the Promotion of Science (JSPS), Grants-in-Aid for Scientific Research on “Innovative Areas (No. 221S0001)” from Japanese Ministry of Education, Culture, Sports, Science and Technology, and the Strategic Research Foundation Grant-aided Project for Private Universities, MEXT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.