miR-34a对NKG2D配体表达的调节作用

miR-34a能够抑制细胞的增殖、迁移和侵袭能力，诱导细胞凋亡，而且其表达能被肿瘤化疗药物通过p53诱导，因此被认为是一个抑癌因子。但是，最近Heinemann等的研究提示miR-34a可能抑制抗肿瘤免疫应答。他们发现miR-34a能够抑制肿瘤细胞表达ULBP-2，ULBP-2是一种NKG2D配体，NKG2D配体与NK细胞或T细胞表面的NKG2D受体结合后，可激活NK细胞或T细胞杀伤表达NKG2D配体的肿瘤细胞。本项目拟研究miR-34a是否能够调节其他NKG2D配体的表达，并深入研究其调节机理，包括：其他NKG2D配体是不是miR-34a的靶基因；miR-34a是否通过其已知的靶基因（包括E2F家族、c-Met、MCYN、Fra-1和Sirt1）调节NKG2D配体的表达；miR-34a是否通过信号识别颗粒（SRP）及其受体调节NKG2D配体的跨膜转运。本研究可能为肿瘤治疗提供新思路。

MicroRNA-34a (miR-34a), a transcriptional target of p53, is a well-known tumor suppressor gene. However, recently it has been found to be able to repress anti-tumor immune response by targeting to ULBP2, an innate immune system ligand for the NKG2D receptor expressed by natural killer (NK) cells and activated CD8(+) T cells. In the proposed study, we aim to address whether miR-34a can regulate the expression of other NKG2D ligands. In addition, we will investigate the molecular mechanisms on how miR-34a regulates the expression of NKG2D ligands, including (1) whether other NKG2D ligands are direct targets of miR-34a; (2) whether the known miR-34a targets, i.e. E2F family,c-Met,MCYN,Fra-1 and Sirt1, can regulate the expression of NKG2D ligands; (3) whether miR-34a can regulate the expression of the signal recognition particle (SRP) and its receptor; (4) whether the expression of NKG2D ligands are regulated by SRP-mediated protein targeting system; and (5) whether miR-34a regulates NKG2D ligands expression via regulating SRP-mediated protein targeting.