Cadherin 6 is activated by Epstein-Barr virus LMP1 to mediate EMT and metastasis as an interplay node of multiple pathways in nasopharyngeal carcinoma.
Cadherin 6 is activated by Epstein-Barr virus LMP1 to mediate EMT and metastasis as an interplay node of multiple pathways in nasopharyngeal carcinoma.
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DOI：
10.1038/s41389-017-0005-7
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发表时间：
2017-12-22
期刊：
影响因子：
6.2
通讯作者：
Lu JH
中科院分区：
文献类型：
--
作者：
Zuo LL;Zhang J;Liu LZ;Zhou Q;Du SJ;Xin SY;Ning ZP;Yang J;Yu HB;Yue WX;Wang J;Zhu FX;Li GY;Lu JH
鼻咽癌(NPC)是一种上皮性恶性肿瘤，以其转移性而在头颈部癌症中享有盛誉。EB病毒(Epstein-Barr Virus，EBV)感染在鼻咽癌的发生发展中起着基础性作用，其发病机制尚不清楚。在这里，我们证明了EBV癌蛋白LMP1通过重新激活黏附分子钙粘蛋白6(CDH6)来驱动鼻咽癌的EMT和转移，CDH6通常发生在胚胎发育中，但在鼻咽癌中的作用未知。CDH6在LMP1阳性的鼻咽癌组织中表达上调，并被确定为上皮特异性miR-203的靶点。LMP1激活的NF-κB通过与miR-203基因启动子区域结合，在转录水平抑制miR-203的表达。CDH6激活可诱导鼻咽癌EMT，促进鼻咽癌转移。CDH6的缺失、NF-κB抑制剂和miR203的过表达均可削弱EMT的作用。鼻咽癌组织中miR-203表达下调与临床转移密切相关。在该事件中，CDH6激活因子Run相关转录因子2(RUNX2)也被EBV激活。由于CDH6和RUNX2都是转化生长因子-β下游的组成部分，CDH6成为包括核因子-κ-B和转化生长因子-β在内的多种信号相互作用的节点蛋白。因此，miR-203的激活对鼻咽上皮细胞维持正常表型具有重要意义。这项研究表明，EBV通过驱动上皮细胞获得恶性特征而进化出复杂的策略，特别是在鼻咽癌转移中，为EBV相关性鼻咽癌的治疗和预后提供了新的生物标志物。
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.
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