Department of Oncology, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Xiangya Hospital, Central South University, Changsha, China.
Cancer Research Institute, School of Basic Medicine Science, Central South University, Changsha, China.
Cancer Sci. 2020 Mar;111(3):857-868. doi: 10.1111/cas.14305. Epub 2020 Feb 5.
Increasing evidence indicates that extracellular vesicles (EVs) play an important role in cancer cell-to-cell communication. The Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1), which is closely associated with nasopharyngeal carcinoma (NPC) pathogenesis, can trigger multiple cell signaling pathways that affect cell progression. Several reports have shown that LMP1 promotes EV secretion, and LMP1 trafficking by EVs can enhances cancer progression and metastasis. However, the molecular mechanism by which LMP1 promotes EV secretion is not well understood. In the present study, we found that LMP1 promotes EV secretion by upregulated syndecan-2 (SDC2) and synaptotagmin-like-4 (SYTL4) through nuclear factor (NF)-κB signaling in NPC cells. Further study indicated that SDC2 interacted with syntenin, which promoted the formation of the EVs, and SYTL4 is associated with the release of EVs. Moreover, we found that stimulation of EV secretion by LMP1 can enhance the proliferation and invasion ability of recipient NPC cells and tumor growth in vivo. In summary, we found a new mechanism by which LMP1 upregulates SDC2 and SYTL4 through NF-κB signaling to promote EV secretion, and further enhance cancer progression of NPC.
越来越多的证据表明，细胞外囊泡（EVs）在癌细胞间通讯中发挥着重要作用。与鼻咽癌（NPC）发病机制密切相关的 Epstein-Barr 病毒（EBV）编码的潜伏膜蛋白 1（LMP1）可触发多种影响细胞进展的细胞信号通路。有几项报道表明，LMP1 促进 EV 的分泌，并且 EV 转运的 LMP1 可增强癌症的进展和转移。然而，LMP1 促进 EV 分泌的分子机制尚不清楚。在本研究中，我们发现 LMP1 通过核因子（NF）-κB 信号通路上调 NPC 细胞中的 syndecan-2（SDC2）和 synaptotagmin-like-4（SYTL4），从而促进 EV 的分泌。进一步的研究表明，SDC2 与 syntenin 相互作用，促进 EV 的形成，而 SYTL4 与 EV 的释放有关。此外，我们发现 LMP1 刺激 EV 的分泌可增强受纳 NPC 细胞的增殖和侵袭能力，并促进体内肿瘤的生长。总之，我们发现了一种新的机制，即 LMP1 通过 NF-κB 信号通路上调 SDC2 和 SYTL4，从而促进 EV 的分泌，并进一步增强 NPC 的癌症进展。
