Genetic Variants In LncRNA H19 Are Associated With The Risk Of Oral Squamous Cell Carcinoma In A Chinese Population

Oral squamous cell carcinoma(OSCC)is a severe disease worldwide,with high morbidity and 5-year mortality of about 50%.In China,an estimated 48,100 incidents and 22,100 death cases due to oral cancer were reported in 2015.In recent year,with the continuous improvement of treatment,the cure rate of OSCC has improved,but the prognosis is still poor.OSCC is one of the main causes contributing to disease related to deaths and a serious one to be resolved in public health.Smoking and alcohol consumption are the main environmental factors affecting the development of OSCC,but only a small fraction of smokers and drinkers develop this disease,suggesting that genetic variants playing vital roles in oral carcinogenesis,individuals with different genetic backgrounds have different risk of OSCC under same environmental exposure.With the advent and improvement of the high throughput technology,genome-wide association studies(GWAS)have revealed several oral cancer susceptibility loci;however,there is yet much of heritability unexplained.Recent studies indicated that the dysregulated expression of long non-coding RNAs(lncRNAs)was implicated in tumorigenesis,suggesting that specific expression of lncRNA may be used as a biomarker of tumor diagnosis and potential drug targets.LncRNAs are defined as RNAs > 200 nucleotides in length and those without encoding proteins,these could serve as pre-transcriptional,transcriptional and post-transcriptional regulators in carcinogenesis.H19 is one of the lncRNAs that participates in the development and progression of malignancies,locating in human chromosome 11p15.5 comprising five exons and four introns.Several studies have shown aberrant expression of H19 in multiple cancers including OSCC.H19 may participates in tumorigenesis and progression by acting as competing endogenous RNA(ceRNA).For example,H19 could promote the development of gallbladder cancer by competitively binding mi R-342-3p to regulate the expression of FOXM1.Single-nucleotide polymorphism(SNP)is a kind of genetic variation that might influence mRNA conformation and gene expression,thereby affecting the function of the gene and disease phenotype.Recently,SNPs in lncRNAs have gained increasing attention for their physiological regulatory functions.The genetic variants of H19 have been identified to be associated with the susceptibility to bladder cancer,gastric cancer,breast cancer and colorectal cancer.To evaluate whether the genetic variants in H19 influence the risk of OSCC in a Chinese population,a case-control study was conducted to analyze functional SNPs in H19,and the study further evaluated the biological effect by bioinformatics prediction and functional experiments.Two SNPs,rs217727 and rs2839701,were found to be associated with the risk of OSCC(rs217727: odds ratio(OR)= 1.32,95%CI= 1.11–1.58,P = 0.002;rs2839701: OR = 1.23,95% CI = 1.04–1.46,P = 0.019).Bioinformatics predicted that rs2839701 C>G might alter the secondary structure of H19.In addition,rs2839701 C>G inhibited the transcription activity and was correlated with the decreased expression of downstream gene MRPL23-AS1.The current results suggested that the SNPs in H19 may play a major role in genetic susceptibility to OSCC.