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

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。

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.