LncRNA-OSER1-AS1的功能性单核苷酸多态性的鉴定及其在非小细胞肺癌中的分子流行病学研究

Lung cancer is the leading cause of cancer-related death worldwide. Although much has been learned from lung cancer-related protein coding genes over the past decades, long non-coding RNAs (lncRNAs), a relatively new and fast evolving family of transcripts accounting for majority of gene activities in the genome, have gained a lot of attention for new discoveries in tumorigenesis of non-small cell lung cancer (NSCLC). On the other hand, single nucleotide polymorphisms (SNPs) have been known to be able to affect the expression and regulatory capacity of lncRNAs. However, the roles of lncRNA SNPs on NSCLC have not been thoroughly investigated. In this study, we selected a list lncRNAs from TCGA public database which showed elevated expression in lung cancer tissue. We extracted SNPs from them and annotated these SNPs using bioinformatic tools. We found a potentially functional SNP rs4142441 located in lncRNA OSER1-AS1. We hypothesize that rs4142441 influences lung cancer risk via regulating the function of OSER1-AS1. We will analyze the association between rs4142441 and NSCLC susceptibility in case-control studies. We will investigate the biological mechanisms about how rs4142441 affects the function of OSER1-AS1 and NSCLC risk in functional studies. The results could possibly provide new biomarkers for the early diagnosis and personalized treatment of NSCLC, and improve our understanding about lung cancer tumorigenesis.

肺癌是中国最普遍的恶性肿瘤之一，其中非小细胞肺癌（NSCLC）约占肺癌总数的80%。长链非编码RNA(lncRNA)在NSCLC的发生发展中起着重要的调控作用，而lncRNA中的单核苷酸多态性(SNPs)可能影响其调控功能。这些SNPs对肺癌易感性的影响尚未得到深入研究，因此本课题拟采用病例对照研究分析lncRNA OSER1-AS1中具有潜在功能的SNP rs4142441与NSCLC易感性的相关度。本课题将运用分子生物学实验探索rs4142441对OSER1-AS1的调控功能以及对肺癌细胞增殖迁移和侵袭产生的影响。研究结果有助于进一步了解肺癌的发病机制，可望为肺癌的个性化治疗提供新的生物标志物。

单核苷酸多态性（SNP）和长非编码RNA（lncRNA）在肺癌的发生发展中具有重要作用。我们以肺癌风险相关的SNP作为线索寻找可以作为肺癌的候选靶标的lncRNA。我们通过NSCLC相关的SNP rs4142441发现了lncRNA OSER1-AS1。OSER1-AS1在肿瘤组织中下调，其低表达与TCGA-LUAD患者中非吸烟者的不良预后有关。细胞试验表明OSER1-AS1通过抑制肺癌细胞的生长，迁移和侵袭而起到抑癌作用。裸鼠皮下成瘤实验和尾静脉注射小鼠转移瘤实验证实OSER1-AS1抑制了体内肿瘤的生长和转移。机制试验显示OSER1-AS1的启动子被MYC抑制，而OSER1-AS1的3'端与microRNA hsa-miR-17-5p和RNA结合蛋白ELAVL1竞争性靶向结合。我们的结果表明OSER1-AS1通过充当ELAVL1诱饵使它远离其靶mRNA发挥了肿瘤抑制功能。我们的发现表明OSER1-AS1可能是NSCLC中的一种新的抑癌lncRNA，有望作为NSCLC的预后生物标志物和治疗的潜在靶标。

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