4.6 Article

The identification of an ESCC susceptibility SNP rs920778 that regulates the expression of lncRNA HOTAIR via a novel intronic enhancer

期刊

CARCINOGENESIS
卷 35, 期 9, 页码 2062-2067

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OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgu103

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资金

  1. National Natural Science Foundation of China [31271382, 91229126, 81201586]
  2. State Key Laboratory of Molecular Oncology [SKL-KF-2013-03]
  3. Beijing Natural Science Foundation [5122020]
  4. Beijing Higher Education Young Elite Teacher Project [YETP0521]
  5. Beijing City Talent Training Project [2012D009016000002]
  6. Program for Changjiang Scholars and Innovative Research Team in University [IRT13045]
  7. Shandong Provincial Natural Science Foundation [Y2008C36]

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Long noncoding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR), which could induce genome-wide retargeting of polycomb-repressive complex 2, trimethylates histone H3 lysine-27 (H3K27me3) and deregulation of multiple downstream genes, is involved in development and progression of esophageal squamous cell carcinoma (ESCC). We hypothesized that the functional single nucleotide polymorphisms (SNP) in HOTAIR may affect HOTAIR expression and/or its function and, thus, ESCC risk. Therefore, we examined the association between three haplotype-tagging SNPs (htSNP) across the whole HOTAIR locus and ESCC risk as well as the functional relevance of an ESCC susceptibility SNP rs920778. Genotypes were determined in three independent case-control sets consisted of 2098 ESCC patients and 2150 controls. The allele-specific regulation on HOTAIR expression by the rs920778 SNP was investigated in vitro and in vivo. We found that the HOTAIR rs920778 TT carriers had a 1.37-fold, 1.78-fold and 2.08-fold increased ESCC risk in Jinan, Shijiazhuang and Huaian populations, respectively, compared with the CC carriers (P = 0.003, 7.7 x 10(-4) and 5.9 x 10(-4)). During inspecting functional relevance of the rs920778 SNP, we identified a novel intronic HOTAIR enhancer locating between +1719bp and +2353bp from the transcriptional start site through reporter assays. Moreover, there is an allelic regulation of rs920778 on HOTAIR expression via this enhancer in both ESCC cell lines and normal esophageal tissue specimens, with higher HOTAIR expression among T allele carriers. These results demonstrate that functional genetic variants influencing lncRNA regulation may explain a fraction of ESCC genetic basis.

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