Twist and epithelial-mesenchymal transition are induced by the EBV oncoprotein latent membrane protein 1 and are associated with metastatic nasopharyngeal carcinoma
Twist and epithelial-mesenchymal transition are induced by the EBV oncoprotein latent membrane protein 1 and are associated with metastatic nasopharyngeal carcinoma
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DOI：
10.1158/0008-5472.can-06-3933
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发表时间：
2007-03-01
期刊：
影响因子：
11.2
通讯作者：
Pagano, Joseph S.
中科院分区：
文献类型：
--
作者：
Horikawa, Toshiyuki;Yang, Jing;Pagano, Joseph S.
鼻咽癌（NPC）是一种与EBV相关的恶性肿瘤，与其他头颈部肿瘤相比具有高度转移性，这可能是因为其与病毒的联系。在这里，我们表明，主要的EBV癌蛋白，潜伏膜蛋白1（LMP 1），诱导上皮间质转化（EMT）通过扭曲，一个主转录调节因子在胚胎发生和新牵连的转移，这反过来，可能有助于高转移性的NPC的字符。在细胞培养模型中，LMP 1可诱导EMT及其相关的细胞运动性和侵袭性，而Twist小干扰RNA的表达逆转了LMP 1诱导的EMT。在不同的EBV感染的细胞系中，Twist的表达与LMP 1的表达相关。显性阴性LMP 1可抑制EBV阳性细胞Twist的表达，而显性阴性LMP 1可诱导EBV阴性鼻咽癌细胞Twist的表达。LMP 1信号通过核因子-KB途径，和IKB超阻遏物抑制LMP 1诱导的Twist。最后，在人NPC组织中，Twist和LMP 1的表达直接相关，并且Twist的表达与临床转移相关。这些结果表明，由人病毒癌蛋白LMP 1诱导的Twist直接有助于NPC的转移性质。
Nasopharyngeal carcinoma (NPC), an EBV-associated malignancy, is highly metastatic compared with other head and neck tumors, perhaps because of its viral link. Here, we show that the principal EBV oncoprotein, latent membrane protein 1 (LMP1), induces epithelial-mesenchymal transition (EMT) via Twist, a master transcriptional regulator in embryogenesis and newly implicated in metastasis, which, in turn, are likely to contribute to the highly metastatic character of NPC. LMP1 could induce EMT and its associated cell motility and invasiveness in a cell culture model, whereas expression of Twist small interfering RNA reversed LMP1-induced EMT. In diverse EBV-infected cell lines, expression of Twist correlates with expression of LMP1. Dominant-negative LMP1 could suppress Twist expression in EBV-positive cells, whereas LMP1 could induce Twist in EBV-negative nasopharyngeal cells. LMP1 signals through the nuclear factor-KB pathway, and an IKB superrepressor inhibited induction of Twist by LMP1. Finally, in human NPC tissues, expression of Twist and LMP1 is directly correlated and expression of Twist is associated with metastasis clinically. These results suggest that induction of Twist by a human viral oncoprotein LMP1 directly contributes to the metastatic nature of NPC.