State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, China, Department of Radiation Oncology, Huaian No. 2 Hospital, Huaian, Jiangsu Province, China, Department of Oncology, Provincial Hospital affiliated to Shandong University, Jinan, Shandong Province, 250021, China, Biochemistry Department of Bethune Military Medical College, Shijiazhuang, Hebei Province, 223002, China and Clinical Laboratory, Shandong Cancer Hospital, Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China.
Department of Radiation Oncology, Huaian No. 2 Hospital, Huaian, Jiangsu Province, China.
Carcinogenesis. 2014 Sep;35(9):2062-7. doi: 10.1093/carcin/bgu103. Epub 2014 Apr 30.
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 × 10(-4) and 5.9 × 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.
长链非编码 RNA（lncRNA）HOX 转录反义 RNA（HOTAIR）可以诱导多梳抑制复合物 2 的全基因组重新靶向，三甲基化组蛋白 H3 赖氨酸-27（H3K27me3）并下调多个下游基因，参与食管鳞状细胞癌（ESCC）的发展和进展。我们假设 HOTAIR 中的功能性单核苷酸多态性（SNP）可能会影响 HOTAIR 的表达和/或功能，从而影响 ESCC 的风险。因此，我们研究了横跨整个 HOTAIR 基因座的三个单倍型标签 SNP（htSNP）与 ESCC 风险以及 ESCC 易感性 SNP rs920778 之间的关联。在三个独立的病例对照集（由 2098 例 ESCC 患者和 2150 例对照组成）中确定基因型。在体外和体内研究了 rs920778 SNP 对 HOTAIR 表达的等位基因特异性调节作用。我们发现，与 CC 携带者相比，HOTAIR rs920778 TT 携带者在济南，石家庄和淮安人群中的 ESCC 风险分别增加了 1.37 倍，1.78 倍和 2.08 倍（P = 0.003，7.7×10（-4）和 5.9×10（-4））。在检查 rs920778 SNP 的功能相关性时，我们通过报告基因检测鉴定了一个位于转录起始位点+1719bp 和+2353bp 之间的新型内含子 HOTAIR 增强子。此外，在 ESCC 细胞系和正常食管组织标本中，rs920778 对 HOTAIR 表达存在等位基因调节，T 等位基因携带者的 HOTAIR 表达更高。这些结果表明，影响 lncRNA 调节的功能性遗传变异可能解释了 ESCC 遗传基础的一部分。
