Zuo L-L, Zhang J, Liu L-Z, Zhou Q, Du S-J, Xin S-Y, Ning Z-P, Yang J, Yu H-B, Yue W-X, Wang J, Zhu F-X, Li G-Y, Lu J-H
The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410080, China.
The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, 410078, China.
Oncogenesis. 2017 Dec 22;6(12):402. doi: 10.1038/s41389-017-0005-7.
Nasopharyngeal carcinoma (NPC) is an epithelial malignancy, which is notorious among head-and-neck cancers with its metastatic feature. Epstein-Barr virus (EBV) infection plays a fundamental role in NPC development with the mechanism is not well understood. Here we demonstrate that EBV oncoprotein LMP1 drives EMT and metastasis of NPC by reactivating the adhesion molecule, cadherin 6 (CDH6), which normally occurs in embryogenesis with unknown role in NPC. CDH6 was found to be upregulated in LMP1-positive NPC tissues, and was identified as a target of the epithelium-specific miR-203. LMP1-activated NF-κB transcriptionally repressed the miR-203 expression by binding to the promoter region of miR-203 gene. CDH6 activation in turn induced EMT and promoted metastasis in NPC. CDH6 depletion, NF-κB inhibitor and miR-203 overexpression were able to impair the EMT effects. The miR-203 downregulation in NPC tissues was strongly associated with metastasis clinically. The CDH6 activator, Runt-related transcription factor 2 (RUNX2), was also activated by EBV in the event. For both CDH6 and RUNX2 are components at TGF-β downstream, CDH6 became a node protein for the interplay of multiple signalings including NF-κB and TGF-β. Therefore, the switch-on of miR-203 was important for nasopharyngeal epithelial cells to maintain normal phenotype. This study demonstrates that EBV has evolved sophisticated strategies by driving epithelial cells to obtain malignant features, particularly in NPC metastasis, providing novel biomarkers for the therapy and prognosis of EBV-associated NPC.
鼻咽癌（NPC）是一种上皮性恶性肿瘤，在头颈部癌症中因其转移特性而声名狼藉。爱泼斯坦-巴尔病毒（EBV）感染在鼻咽癌的发生发展中起重要作用，但其机制尚不清楚。在此，我们证明EBV癌蛋白LMP1通过重新激活黏附分子钙黏蛋白6（CDH6）来驱动鼻咽癌的上皮-间质转化（EMT）和转移，CDH6通常在胚胎发育过程中出现，在鼻咽癌中的作用尚不清楚。研究发现CDH6在LMP1阳性的鼻咽癌组织中上调，并被确定为上皮特异性miR-203的靶标。LMP1激活的核因子κB（NF-κB）通过与miR-203基因的启动子区域结合，转录抑制miR-203的表达。CDH6的激活进而诱导鼻咽癌的EMT并促进转移。CDH6的缺失、NF-κB抑制剂和miR-203的过表达均能削弱EMT效应。鼻咽癌组织中miR-203的下调在临床上与转移密切相关。CDH6激活剂，即 runt相关转录因子2（RUNX2），在该事件中也被EBV激活。由于CDH6和RUNX2都是转化生长因子-β（TGF-β）下游的成分，CDH6成为包括NF-κB和TGF-β在内的多种信号相互作用的节点蛋白。因此，miR-203的开启对于鼻咽上皮细胞维持正常表型很重要。本研究表明，EBV通过驱动上皮细胞获得恶性特征，特别是在鼻咽癌转移方面，已经进化出复杂的策略，为EBV相关鼻咽癌的治疗和预后提供了新的生物标志物。
