内质网应激诱导的microRNA与细胞节律紊乱在原癌基因MYC引起的肿瘤中的作用

Circadian rhythm is important for cell growth, proliferation, protein synthesis and metabolism. There are multiple lines of evidence suggesting that deregulation of peripheral circadian rhythms contribute to neoplastic cell growth, altered cellular metabolism and tumorigenesis.We observed that Endoplasmic Reticulum (ER) stress disrupts circadian rhythms via microRNA-211.In the context of neoplastic growth, oncogenes such as c-Myc trigger ER stress and activate the Unfolded Protein Response (UPR) signaling, promoting tumorigenesis. However, the coordination and interaction among Oncogene activation,ER stress and circadian oscillation in the context of tumorigenesis are largely unknown. .In this study, we are going to verify whether ER stress disrupt peripheral circadian oscillation both in vitro and in vivo. Then we will screen the ER stress associated microRNAs by microarray and identify their specific targets involved in circadian rhythms via HITS-CLIP. Further we will use Burkitt’s lymphoma cells，mouse model and Oncomine patients database interrogating that the ER stress dependency and correlation among miR-211, loss of circadian oscillation，tumor growth in the context of myc-driven malignancy. At last we will try to target activated ER stress or abnormal miR-211 expression by inhibitors to rescue circadian rhythms and suppress tumor proliferation. This study could provide a new potential therapy for Myc- (perhaps also other oncogenes) driven malignancy.

细胞内分子水平的昼夜节律对正常细胞的增殖、蛋白合成以及代谢等都有重要作用。肿瘤细胞大多缺失昼夜节律或者节律紊乱。我们的研究发现内质网应激可以通过microRNA-211而引起细胞节律变化。原癌基因c-myc的激活可以刺激内质网的应激反应，影响肿瘤细胞的生长增殖，但是内质网和细胞节律信号之间的交互作用机制以及它们在癌细胞增殖过程中的作用尚不清楚。本项目将在培养的细胞和动物模型中检测内质网应激是否导致细胞节律紊乱，并筛选和鉴定参与内质网应激的miRNAs，并通过HITS-CLIP寻找与节律相关的靶基因；结合Oncomine大数据，在Burkitt's淋巴瘤病人样本和细胞系中验证这些靶基因的功能，最后探讨应用内质网应激的抑制剂及针对miRNA的方法是否可以通过抑制MYC而改善细胞节律，从而抑制肿瘤细胞的增殖。本研究将为MYC引起的肿瘤的治疗提供理论依据。