lncRNA MALAT1 作为竞争性内源RNA调控骨髓瘤肿瘤生长及血管新生的机制研究

项目名称： lncRNA MALAT1 作为竞争性内源RNA调控骨髓瘤肿瘤生长及血管新生的机制研究

项目编号： No.81500168

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 严晗

作者单位： 华中科技大学

项目金额： 18万元

中文摘要： 长链非编码RNA（lncRNA）可作为竞争性内源RNA，通过与miRNA结合促进肿瘤的发生发展，追踪文献表明lncRNA在多发性骨髓瘤（MM）中的功能和调控机制研究迄今未见报道。前期我们发现lncRNA MALAT1在多种MM细胞系上表达上调，下调其表达可显著抑制MM细胞增殖。生物信息学预测MALAT1可能与miRNA-15a/16结合，而后者已被课题组证实通过靶向VEGF/cyclinD1等调控MM血管新生和肿瘤生长，据此我们推测MALAT1通过竞争性结合miRNA-15a/16，解除其对靶基因的抑制，促进MM发生发展。本课题将比较正常人和MM患者上MALAT1的表达水平，初步揭示其临床意义，然后在细胞和活体动物水平验证这一机制是否参与调控MM肿瘤生长和血管新生。本研究将两种非编码RNA功能结合，首次探讨了MALAT1通过竞争性内源RNA活性在MM发病机制中的作用，为MM诊治提供新思路。

中文关键词： 多发性骨髓瘤；长链非编码RNA；微小RNA；竞争性内源RNA；血管新生

英文摘要： Aberrant expression of long non-coding RNAs (lncRNAs) is associated with various human cancers. Recently, reports have demonstrated that lncRNAs may function as a competing endogenous RNAs (ceRNAs) to miRNAs. So far, the functional role and mechanism of lncRNA in multiple myeloma (MM) are unknown. Our preliminary data showed that the levels of lncRNA MALAT1 were up-regulated in various MM cell lines. Moreover, the proliferation ability of MM cells was inhibited after treated with MALAT1 siRNA. Bioinformatics prediction for miRNA recognition sequences in MALAT1 indicating the presence of a putative binding site for miRNA-15a/16, which has been proved to regulate proliferation and angiogenesis in MM by targeting VEGF/cyclinD1.Therefore, we speculate that MALAT1 may function as a ceRNA to regulate VEGF/cyclinD1 levels by sponging miRNA-15a/16 and consequently promote angiogenesis and tumor growth in MM. Detection and comparison of MALAT1 expression levels in CD138+ cells from healthy donors and MM patients will be carried out by qRT-PCR analysis and then its relationship with clinical significance of MM will be evaluated. Furthermore, luciferase reporter assay and RIP assay will be used to verify that MALAT1 competes for binding to miRNA-15a/16 in an Argonaute-dependent manner, thereby affecting the derepression of VEGF/cyclinD1. Finally, the role of the ceRNA regulatory network, MALAT1-miRNA-15a/16-VEGF/cyclinD1, in regulating tumor growth and angiogenesis will be tested in vitro and in vivo. This study will provide a novel insight into the role of ceRNA regulatory network in cancer, and a novel molecular target for MM.

英文关键词： multiple myeloma;long non-coding RNA;microRNA;competitive endogenous RNA;angiogenesis