Jab1绑定lncRNA ANRIL诱导EMT调控鼻咽癌侵袭转移的机制研究

Nasopharyngeal carcinoma (NPC), originating from the epithelial lining of the nasopharynx, is a squamous-cell carcinoma, many patients with NPC will develop distant metastasis, and the prognosis is very poor once metastasis occurs. Jab1 and lncRNA are involved in the progression of NPC, however, the role of Jab1 in invasion and metastasis remains to be clarified. Our preliminary experiment suggested that Jab1 was overexpressed in metastatic NPC tissues compared with non-metastatic tissues; Jab1 binds to lncRNA ANRIL in NPC cells; Jab1 and ANRIL not only affected the invasion and metastasis of NPC but also regulated EMT (Epithelial to Mesenchymal Transition) associated signal molecule. Collectively, we assume that Jab1 regulates invasion and metastasis by interacting with ANRIL in NPC. Our study will be divided into two parts: (1) to illuminate the biological function and clinical significance of Jab1 and ANRIL in invasion and metastasis; (2) to reveal the mechanism by which Jab1 interacts with ANRIL and subsequently regulates EMT associated genes and proteins expression and function. (3) to study the role of Jab1 and ANRIL in the whole course of EMT in primary tumor-circulating tumor cells (CTCs)-metastasis tumor. With experiments on clinical level, cellular level and mouse model, we intend to elucidate the role of Jab1 and ANRIL in regulating the invasion and metastasis of NPC and explore its clinical application, which will provide new targets and intervention strategies for the treatment of metastatic NPC.

鼻咽癌（NPC）系鼻咽部黏膜上皮细胞发生的恶性肿瘤，易侵袭转移。Jab1和长链非编码RNA（lncRNA）参与了NPC进展，但在侵袭转移中作用不明。我们前期发现：转移NPC组织中Jab1水平明显高于原位肿瘤组织；NPC细胞内Jab1蛋白特异性结合lncRNA ANRIL；Jab1和ANRIL不仅影响细胞的侵袭能力，还影响上皮间质转化（EMT）信号分子表达。因此，我们推测Jab1绑定ANRIL调控NPC侵袭转移。本项目拟开展如下研究：（1）Jab1绑定ANRIL促进NPC侵袭转移的临床意义和生物学功能；（2）Jab1与ANRIL相互作用的分子机理和在调节EMT相关基因和蛋白的表达、功能发挥中的作用。（3）Jab1绑定ANRIL在原位灶-外周血循环肿瘤细胞-转移灶的EMT全程作用。在临床、体外和体内三个层面阐明Jab1绑定ANRIL促进侵袭转移的分子机制，为转移性NPC的靶向治疗提供新策略。

鼻咽癌（NPC）系鼻咽部黏膜上皮细胞发生的恶性肿瘤，易侵袭转移。Jab1信号通路参与了NPC演进，但在侵袭转移中作用不明。本项目在肿瘤原位组织研究肿瘤浸润T淋巴细胞特异性lncRNAs，评估其在肿瘤分级，大小、淋巴结转移、远处转移以及生存预后的作用。在NPC细胞富集区域、免疫细胞富集区域及正常上皮细胞富集区域探索Jab1和铜死亡基因对NPC患者的影响并根据铜死亡基因表达量对NPC患者不同区域内部进行分型。经单因素cox回归，lasso回归及多因素cox回归筛选预后铜死亡基因相关lncRNA并构建预后模型。通过生存分析，风险曲线，相关性分析，TMB，突变频率及类型来评估模型预测效果。Jab1和铜死亡基因的相互作用，影响了NPC微环境不同区域的化疗效果。筛选在不同Jab1表达状态下预后lncRNA，并构建了预后模型。本项目研究循环微环境组分联合炎症免疫标志物在各个组别NPC患者之间进行比较研究。高PLR、高白细胞计数高红细胞分布宽度、高龄和远处转移是鼻咽癌患者预后的独立危险因素。研究发现，EBV感染影响了淋巴细胞内Jab1表达。鼻咽癌临床分期越高，CD8+和CD4+淋巴细胞内Jab1的表达水平越高。Ki67增殖指数越高，CD8+和NK细胞内Jab1的表达水平越高。外周血循环肿瘤细胞（CTC）计数是总生存期预后不良的独立因素。肿瘤患者治疗前后CTC计数与血液微环境参数显著相关。研究表明，Jab1通过相关靶基因参与调控鼻咽癌的侵袭转移。本项目系统地探讨了Jab1在肿瘤演进的作用及机制，将为鼻咽癌研究提供关键靶点信息，同时为临床转化研究提供诊断、监测及治疗新策略。