Epstein-Barr virus-encoded latent membrane protein 1 impairs G2 checkpoint in human nasopharyngeal epithelial cells through defective Chk1 activation.
Epstein-Barr virus-encoded latent membrane protein 1 impairs G2 checkpoint in human nasopharyngeal epithelial cells through defective Chk1 activation.
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DOI：
10.1371/journal.pone.0039095
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Tsao SW
中科院分区：
文献类型：
--
作者：
Deng W;Pang PS;Tsang CM;Hau PM;Yip YL;Cheung AL;Tsao SW
鼻咽癌（NPC）是东南亚特别是中国南方地区的常见癌症。 EBV 感染与 NPC 密切相关，长期以来被认为在 NPC 的发展中发挥着病因作用。然而，EBV 在鼻咽上皮细胞恶性转化中的作用仍然是个谜。目前关于鼻咽癌发展的假设是，含有基因改变的癌前鼻咽上皮细胞支持 EBV 感染，并且 EBV 基因的表达会诱导进一步的基因组不稳定，从而促进鼻咽癌的发展。潜伏膜蛋白 1 (LMP1) 是一种有据可查的 EBV 编码癌基因。 LMP1 与人类上皮恶性肿瘤有关，但 LMP1（尤其是鼻咽细胞）的致癌作用机制尚不清楚。在这里，我们观察到鼻咽上皮细胞中LMP1的表达损害了G2检查点，导致γ射线照射后在中期形成未修复的染色单体断裂。我们进一步发现，有缺陷的 Chk1 激活参与了表达 LMP1 的鼻咽上皮细胞中 G2 检查点缺陷的诱导。 G2 检查点受损可能会导致无中心断裂染色单体的丢失以及退出有丝分裂的子细胞中断裂中心染色单体的繁殖，从而促进染色体不稳定。我们的研究结果表明，LMP1 表达会促进基因毒性应激下细胞的基因组不稳定。阐明 LMP1 诱导的鼻咽上皮细胞基因组不稳定性的机制将有助于理解 EBV 感染在鼻咽癌发育中的作用。
Nasopharyngeal carcinoma (NPC) is a common cancer in Southeast Asia, particularly in southern regions of China. EBV infection is closely associated with NPC and has long been postulated to play an etiological role in the development of NPC. However, the role of EBV in malignant transformation of nasopharyngeal epithelial cells remains enigmatic. The current hypothesis of NPC development is that premalignant nasopharyngeal epithelial cells harboring genetic alterations support EBV infection and expression of EBV genes induces further genomic instability to facilitate the development of NPC. The latent membrane protein 1 (LMP1) is a well-documented EBV-encoded oncogene. The involvement of LMP1 in human epithelial malignancies has been implicated, but the mechanisms of oncogenic actions of LMP1, particularly in nasopharyngeal cells, are unclear. Here we observed that LMP1 expression in nasopharyngeal epithelial cells impaired G2 checkpoint, leading to formation of unrepaired chromatid breaks in metaphases after γ-ray irradiation. We further found that defective Chk1 activation was involved in the induction of G2 checkpoint defect in LMP1-expressing nasopharyngeal epithelial cells. Impairment of G2 checkpoint could result in loss of the acentrically broken chromatids and propagation of broken centric chromatids in daughter cells exiting mitosis, which facilitates chromosome instability. Our findings suggest that LMP1 expression facilitates genomic instability in cells under genotoxic stress. Elucidation of the mechanisms involved in LMP1-induced genomic instability in nasopharyngeal epithelial cells will shed lights on the understanding of role of EBV infection in NPC development.