The A Allele at rs13419896 of EPAS1 Is Associated with Enhanced Expression and Poor Prognosis for Non-Small Cell Lung Cancer.
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.
Department of Radiation Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
Andika C
AC
Putra
Division of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
Hidetaka
H
Eguchi
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
Kian Leong
KL
Lee
Department of Radiation Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
Yuko
Y
Yamane
Department of Radiation Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
Ewita
E
Gustine
Division of Clinical Oncology and Respiratory Medicine, Department of Internal Medicine, School of Medicine, Shimane University, Shimane, Japan.
Takeshi
T
Isobe
Department of Molecular and Cellular Pharmacology, Graduate School of Medicine, Gunma University, Gunma, Japan.
Masahiko
M
Nishiyama
Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan.
Keiko
K
Hiyama
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute, Stockholm, Sweden.
Lorenz
L
Poellinger
Department of Radiation Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
Keiji
K
Tanimoto
D000368:Aged; D000483:Alleles; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D017930:Genes, Reporter; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016019:Survival Analysis; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1