LMP1-positive extracellular vesicles promote radioresistance in nasopharyngeal carcinoma cells through P38 MAPK signaling
LMP1-positive extracellular vesicles promote radioresistance in nasopharyngeal carcinoma cells through P38 MAPK signaling
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LMP1阳性细胞外囊泡通过P38 MAPK信号促进鼻咽癌细胞的放射抗性
DOI：
10.1002/cam4.2506
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发表时间：
2019
期刊：
影响因子：
4
通讯作者：
Lifang Yang
中科院分区：
文献类型：
--
作者：
Zhibao Zhang;Xuehui Yu;Zhuan Zhou;Bo Li;Jinwu Peng;Xia Wu;Xiangjian Luo;Lifang Yang
放射抵抗一直是临床环境中有效治疗鼻咽癌（NPC）的障碍之一。EB-巴尔病毒（Epstein-Barr virus，EBV）编码的潜伏膜蛋白1（latent membrane protein 1，LMP 1）在鼻咽癌中表达，对鼻咽癌的放射抵抗有重要作用。它已在细胞外囊泡（EV）或外泌体中检测到，并显示出促进肿瘤增殖和侵袭潜力。然而，LMP 1阳性EV是否可以赋予癌细胞辐射抗性以及用于促进辐射抗性的机制需要阐明。在本研究中，数据显示来自LMP 1阳性NPC细胞的EV可以诱导受体NPC细胞增殖和侵袭，并抑制凋亡，特别是促进辐射抗性。此外，LMP 1可增加LMP 1阳性EV的分泌。此外，LMP 1通过激活受体细胞中的P38 MAPK信号通路发挥其致癌作用，抑制P38活性可有效地恢复鼻咽癌细胞对电离辐射（IR）的敏感性。最后，我们发现LMP 1阳性EV可以促进肿瘤生长，P38抑制消除了体内的这种促进作用，EV形成与NPC患者的预后不良相关。这些结果表明，少数表达LMP 1的细胞可以通过潜在地影响感染的宿主并调节肿瘤微环境来增强NPC细胞的辐射抗性。
Radioresistance has been one of the impediments to effective nasopharyngeal carcinoma (NPC) therapy in clinical settings. Epstein‐Barr virus (EBV) encoded latent membrane protein 1 (LMP1) is expressed in NPC and has potent effects on radioresistance. It has been detected in extracellular vesicles (EVs) or exosomes and shown to promote tumor proliferation and invasive potential. However, whether LMP1‐positive EVs can confer radioresistance to cancer cells and the mechanism used to promote radioresistance need to be elucidated. In this study, the data showed that EVs derived from LMP1‐positive NPC cells could induce recipient NPC cell proliferation and invasion and suppress apoptosis, especially promoting radioresistance. In addition, LMP1 could increase the secretion of LMP1‐positive EVs. Furthermore, transmitted LMP1 subsequently performed its oncogenic functions through activating P38 MAPK signaling in recipient cells, and inhibiting P38 activity could efficaciously restore the sensitivity of NPC cells to ionizing radiation (IR). Finally, we found that LMP1‐positive EVs could promote tumor growth and P38 inhibition eliminates this promoting effect in vivo, and EV formation is associated with a poor prognosis in NPC patients. These results showed that a few cells expressing LMP1 could enhance the radioresistance of NPC cells through potentially impacting the infected host and also modulating the tumor microenvironment.