The identification of an ESCC susceptibility SNP rs920778 that regulates the expression of lncRNA HOTAIR via a novel intronic enhancer.
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.
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.
Xiaojiao
X
Zhang
Department of Radiation Oncology, Huaian No. 2 Hospital, Huaian, Jiangsu Province, China.
Liqing
L
Zhou
Department of Oncology, Provincial Hospital affiliated to Shandong University, Jinan, Shandong Province, 250021, China.
Guobin
G
Fu
Biochemistry Department of Bethune Military Medical College, Shijiazhuang, Hebei Province, 223002, China and.
Fang
F
Sun
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.
Juan
J
Shi
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.
Jinyu
J
Wei
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.
Chao
C
Lu
Clinical Laboratory, Shandong Cancer Hospital, Shandong Academy of Medical Sciences, Jinan, Shandong Province, 250117, China.
Changchun
C
Zhou
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.
Qipeng
Q
Yuan
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 yangm@mail.buct.edu.cn.
Ming
M
Yang
D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D004742:Enhancer Elements, Genetic; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism; D000077277:Esophageal Squamous Cell Carcinoma; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007438:Introns; D020641:Polymorphism, Single Nucleotide; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors
C561566:HOTAIR long untranslated RNA, human; D062085:RNA, Long Noncoding