长非编码RNA BC032469调控胃癌细胞hTERT表达的分子机制研究

In our previous study, it has been proved that the activation of hTERT participated in the whole process of tumor's genesis and development. Till now, relative research about post-transcriptional control of hTERT mostly concentrated on miRNA, while how miRNA is regulated remains to be unclear. Under the financial assistance of National Natural Sciences Fund, we found that multiple miRNAs can suppress the expression of hTERT by combining with hTERT 3'UTR. Meanwhile, by bioinformatics technology, it has been found that long non-coding RNA BC032469 (lncRNA BC032469) near hTERT gene together with seed area of miRNAs had several tandem complementary sequences; these miRNAs was negatively correlated to the expression of lncRNA in stomach cancer tissue, which indicated that lncRNA BC032469 may down-regulate miRNAs by endogenous sponge effect, then promoting the expression of hTERT. This study is planning to clarify the molecule mechanism of lncRNA controlling miRNAs and its role in the activation of hTERT, by luciferase experiment, RNA-interfering technique and animal experiment, etc. which will provide a new target point for tumor prevention and cure based on hTERT.

文献及我们的研究证实端粒酶逆转录酶(hTERT)的活化参与了肿瘤发生发展的全过程。目前有关hTERT转录后调控多集中在miRNA，而相关miRNA又是如何被调控的并不清楚。在国家自然科学基金资助下，我们发现多个miRNAs可以通过与hTERT 3'UTR结合抑制hTERT的表达，同时生物信息学分析发现hTERT基因附近的长非编码RNA BC032469 (lncRNA BC032469)与miRNAs的种子区有数个串联的互补序列，并发现上述miRNAs和lncRNA在胃癌组织中的表达呈负相关，提示lncRNA BC032469可能通过内源性"海绵效应"下调miRNAs，从而促进hTERT的表达.本课题拟采用荧光素酶实验、RNA干扰技术及动物实验等，阐明lncRNA调控miRNAs的分子机制及在hTERT活化中的作用，为基于hTERT的肿瘤防治提供新的靶点。

长链非编码RNA是新兴的基因调控成员，与癌症的发展有关。我们探讨在胃癌发生发展中发挥重要作用的lncRNA以及研究它的机制，我们筛选在胃癌组织及癌旁组织的lncRNAs，并对其临床病理特点进行评估。lncRNAbc032469 在胃癌组织中的表达上调，与临床与肿瘤大小相关，并且高表达lncRNA的胃癌患者的分化及生存期较短。下调lncRNA bc032469显著抑制体外和体内增殖。lncRNA bc032469可以直接结合mir-1207-5p有效发挥一个海绵吸附作用，从而释放mir-1207-5p对人端粒酶逆转录酶（hTERT）的阻遏。因此，bc032469可以影响mir-1207-5p依赖的hTERT基因表达，提示可能为胃癌不良预后的标志物。