p53调控的lincRNA-GAPP3抑制细胞自噬的分子机制及其在肿瘤发生中的作用

Aberrant autophagy is important for tumorigenesis, but the regulation mechanism of autophagy is still elusive. The roles of lncRNAs have attracted more and more attention recently, and whether lncRNA is involved in the regulation of autophagy and plays a key role in tumorigenesis becomes a research focus. Our previous study has showed that lincRNA-GAPP3, an lncRNA located between genes, is down-regulated in autophagy; knockdown of lincRNA-GAPP3 can enhance autophagy; lincRNA-GAPP3 interacts with Beclin-1, a key regulator of autophagy, and the promoter of lincRNA-GAPP3 contains a potential p53 binding site. Based on previous work, this project intends to study at different levels and by use of various methods. The main contents include: 1) The molecular mechanisms of autophagy inhibition by lincRNA-GAPP3; 2) Specific mechanisms of regulation of lincRNA-GAPP3 by p53; 3) Whether lincRNA-GAPP3 mediates the regulation of p53 on autophagy; 4) The role of lincRNA-GAPP3 inhibited autophagy in tumorigenesis. Exploiting the mechanisms of lncRNAs in regulation of autophagy will help understand tumorigenesis from a new angle, and provide new strategies for tumor therapy.

自噬异常对肿瘤发生至关重要，但自噬调控机制尚存诸多未解之谜。近年来长链非编码RNA(lncRNA)功能倍受关注，lncRNA是否参与自噬调控以及是否在肿瘤发生中起关键作用成为重要科学问题。前期研究发现自噬情况下lincRNA-GAPP3（一个位于基因间的lncRNA）表达下调，敲低其表达促进细胞自噬；lincRNA-GAPP3可与自噬关键蛋白Beclin-1结合而且其启动子区域存在肿瘤抑制因子p53结合位点。本项目将以此为基础，多水平多方法深入研究：1) lincRNA-GAPP3抑制细胞自噬的分子机制；2) p53调控lincRNA-GAPP3表达的具体机制；3)lincRNA-GAPP3是否介导p53对自噬调控；4）lincRNA-GAPP3抑制自噬在肿瘤发生中的作用。以期更好地诠释lncRNA调控细胞自噬的关键机制, 从全新的角度揭示肿瘤发生的分子基础，为肿瘤治疗提供新的思路和手段。

P53是非常重要的肿瘤抑制因子，其在肿瘤发生过程中的功能倍受关注。长链非编码RNA(lncRNA)在肿瘤发生中起重要作用，但目前对其作用机制知之甚少。p53及其调控的lncRNA调控肿瘤发生的机制成为重要的科学问题。在本项目的资助下，我们首先发现GUARDIN(基于其在维持细胞生存中的作用我们自己命名的)是一个受p53转录调控的lncRNA，当GUARDIN被敲除后，DNA损伤增加，细胞逐渐发生凋亡。深入研究发现GUADIN同时通过两种机制参与维护生理稳态条件下和暴露于外源基因毒性应激条件下基因组的完整性。1)，GUARDIN作为“分子海绵”吸附微小RNA 23a (miRNA-23a)，促进端粒重复序列结合因子2(TRF2)的表达而减少端粒末端结构的破坏；2)，GUARDIN可以作为“分子支架”增加乳腺癌1号基因(BRCA1)与BRCA1相关的RING结构域蛋白1(BARD1)结合而稳定BRCA1，维持细胞的DNA损伤修复能力。该研究成果是长链非编码RNA参与DNA损伤修复领域的重要研究进展，首次发现受p53调控的长链非编码RNA参与DNA损伤修复，维护基因组稳定，找到了一个潜在的肿瘤治疗干预靶点GUARDIN，提供了全新角度去探讨长链非编码RNA与肿瘤发生的关系，研究成果有望为肿瘤临床治疗策略提供新思路。在本项目的资助下，我们已经在Nature Cell Biology等杂志上发表论文6篇，标注了基金号。