EB病毒癌蛋白LMP1通过下调microRNA-203诱导上皮间质转化及其调控机制的研究

与EB病毒高度相关及高度转移性是鼻咽癌（NPC）的重要特征。本项目前期研究发现，EBV通过其癌蛋白LMP1在上皮细胞及NPC中下调miR-203的表达、从而促进肿瘤发生，这种作用与转录因子NF-κB信号通路有关。据报道，NF-κB和miR-203均可通过促进或抑制上皮间质转化（EMT）参与肿瘤的侵袭转移，但是它们之间的关系尤其是在EBV相关性NPC中，miR-203的上下游通路在参与EMT中的调控机制不清楚。本项目以EBV感染的上皮和NPC细胞模型为基础，研究NF-κB是否直接抑制miR-203基因转录或通过其它EMT相关分子下调miR-203及机制，研究miR-203对肿瘤转移相关的靶基因如CDH6的调节及NF-κB是否通过CDH6调节miR-203表达，研究从LMP1到EMT通路中关键分子间的相互关系，并在临床样本中进行检测验证。本研究为EBV在NPC发生中的病因学机制提供新的依据。

Nasopharyngeal carcinoma (NPC) is notorious among head and neck cancers since it is highly associated with Epstein-Barr virus and highly metastatic. Our previous study demonstrated that miR-203 was significantly decreased with a role of EBV-encoded oncoprotein latent membrane protein (LMP1) both in epithelial and NPC cells. It was also showed that the miR-203 downregulation is related to a promoted tumor incidence in a manner depending on the NF-κB pathway. NF-κB and miR-203 are reported to be involved in the invasive and metastatic cancers by facilitating or inhibiting epithelial-mesenchymal transition (EMT) respectively, whereas it is not clear for their relationship. The regulatory mechanism of EMT at the upstream and downstream of miR-203 is largely to be clarified, especially in the EBV-associated NPC. Based on our previous results and the models of EBV-infected epithelial and NPC cells, this project would focus on the regulatory mechanism of EMT induced by EBV-LMP1 via the miR-203 downregulation. The mechanism is to be explored on that NF-κB inhibits the transcription directly or through EMT-related transcription factor indirectly. Whether CHD6, which is potentially related to EMT, is a novel target gene of miR-203 and CDH6 and is also regulated by NF-κB would be studied. The interrelationship among the crucial factors within the whole pathway from LMP1 to EMT would be confirmed both in the cell model study and in clinical samples. The study of this project would provide further evidence for our fully understanding about the EBV-associated etiology during the development of NPC.