The A Allele at rs13419896 of EPAS1 Is Associated with Enhanced Expression and Poor Prognosis for Non-Small Cell Lung Cancer.
The A Allele at rs13419896 of EPAS1 Is Associated with Enhanced Expression and Poor Prognosis for Non-Small Cell Lung Cancer.
复制标题
DOI：
10.1371/journal.pone.0134496
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Tanimoto K
中科院分区：
文献类型：
--
作者：
Putra AC;Eguchi H;Lee KL;Yamane Y;Gustine E;Isobe T;Nishiyama M;Hiyama K;Poellinger L;Tanimoto K
缺氧诱导因子-2 α（HIF-2α，EPAS 1）在肿瘤进展中起重要作用，是非小细胞肺癌（NSCLC）预后不良的生物标志物。然而，EPAS 1过表达的分子机制尚未完全了解。我们探讨了一个单核苷酸多态性（SNP）的作用，rs 13419896位于内含子1的EPAS 1基因的表达调控。生物信息学分析表明，包括rs 13419896 SNP的区域在调节EPAS 1基因表达中起作用，并且SNP改变转录因子的结合活性。体外分析表明，一个片段含有SNP位点的功能作为一个调控区，一个片段与A等位基因表现出更高的反式激活活性比一个与G，特别是在过度表达的c-Fos或c-Jun的存在下。此外，NSCLC患者的A等位基因表现出较差的预后比那些与G在SNP，即使调整后的各种变量。总之，EPAS 1基因的遗传多态性可能导致其基因表达水平的变化，从而驱动癌症的进展，并作为NSCLC的预后标志物。
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.