ZBTB7A/lncRNA-ANRIL反馈环路经由SREBP1-FASN脂质代谢通路调控鼻咽癌侵袭转移的机制研究

鼻咽癌（NPC）复发及转移严重影响患者预后。前期研究发现稳定敲减原癌基因ZBTB7A表达导致NPC细胞致癌力、迁移侵袭力代偿增强；经lncRNA芯片检测、生物信息学分析及组织验证，ZBTB7A表达下降导致lncRNA-ANRIL表达上调，SREBP1和FASN的RNA水平表达下调，但作用机制不清楚。基于lncRNA-ANRIL与ZBTB7A潜在的反馈关系，我们假设：该反馈环路经SREBP1-FASN调控NPC发展。本项目拟构建稳定敲减及稳定过表达ZBTB7A或lncRNA-ANRIL的NPC细胞亚株，并对这两靶点进行不同干预的组合，体内外实验观察细胞致癌力及侵袭转移能力的变化，分析ZBTB7A与lncRNA-ANRIL相互作用关系及对脂质代谢关键通路SREBP1-FASN影响，采用脂质生成抑制剂作用不同干预细胞株，观察细胞脂质代谢变化，为通过该类抑制剂治疗复发性及转移性NPC提供实验依据。

The recurrence and metastasis of nasopharyngeal carcinomas (NPC) severely influence NPC patients’ prognosis. In the previous study, ZBTB7A, a member of the POZ/BTB and Krüppel (POK) family of transcription factors, was a proto-oncogene of NPC. However, ZBTB7A being stably knocked down could vicariously promote carcinogenicity, migration and invasion of NPC cells. We found deceased ZBTB7A caused up-regulated long noncoding RNA (lncRNA) antisense non-coding RNA in the INK4 locus (ANRIL), down-regulated the expressions of sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FASN) at RNA level by detecting lncRNA chips, analyzing bioinformatics and validating from NPC biopsy specimens. But the regulatory mechanisms are still unclear. Basing on the potential feedback between lncRNA-ANRIL and ZBTB7A, we assume that the feedback loop regulates NPC progress via SREBP1-FASN. We will separately construct NPC sublines being stably down-regulated ZBTB7A or lncRNA-ANRIL, up-regulated ZBTB7A or lncRNA-ANRIL in the study. LncRNA-ANRIL will be transiently up-regulated or down-regulated in the NPC sublines being stably down-regulated or up-regulated ZBTB7A. ZBTB7A will be transiently down-regulated or up-regulated in the NPC sublines being stably up-regulated or down-regulated lncRNA-ANRIL. The changes of carcinogenicity, invasion and metastasis of the NPC cells will be observed in vivo and in vitro. Then we will analyze the relationship between ZBTB7A and lncRNA-ANRIL, and their effect on SREBP1-FASN which is a key pathway of lipid metabolism. At last, we will add some inhibitors of lipogenesis in the cell sublines being changed the levels of ZBTB7A and lncRNA-ANRIL, and observe the changes of lipid metabolism. The study will provide experimental evidence for treating recurrence and metastasis of NPC through the inhibitors of lipogenesis.