STIM1钙信号调控的外泌体传递LMP1对鼻咽癌肿瘤血管生成的调控机制

EB病毒编码LMP1通过重塑肿瘤微环境推动鼻咽癌进展。我们既往工作表明:阻断EBV阳性鼻咽癌细胞的钙池操控钙内流(SOCE)可明显抑制其促血管生成作用，进一步在表达LMP1细胞上阻断SOCE可干扰其对血管内皮的重塑，但机制未明。我们最近发现STIM1依赖的SOCE钙信号对携带LMP1外泌体释放具有调控作用，受体内皮细胞摄取外泌体传递LMP1后PI3K通路活化及其所调控的血管新生明显增强。据此推断：受STIM1钙信号调控的LMP1外泌体通过激活内皮细胞PI3K/Akt通路参与肿瘤血管的重塑。本课题通过研究STIM1信号对LMP1外泌体释放，受体内皮细胞摄取LMP1后PI3K/Akt通路的激活及对增殖、迁徙及渗透性等内皮表型的调控，并运用前期成功构建的转基因斑马鱼模型，在单细胞水平上阐明LMP1外泌体传递对鼻咽癌-血管内皮细胞交互作用的调控，进一步揭开EB病毒感染对鼻咽癌肿瘤血管重塑的机制。

Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) promotes the progression of nasopharyngeal carcinoma (NPC) by remodeling tumor microenvironment. Our previous work showed that blockage of the store-operated calcium entry (SOCE) in EBV-positive NPC cells significantly inhibits tumor angiogenesis. Furthermore, blockage of SOCE disturbs the remodeling of vascular endothelium by LMP1-expressing NPC cells. However, the underlying mechanism remains unclear. Our recent works indicated that release of the exosomes harboring LMP1 is regulated by STIM1-dependent SOCE Ca2+ signaling, and the tumor angiogenesis is enhanced while PI3K activation is promoted in the recipient endothelial cells after uptake of the exosomal LMP1. We thus hypothesize that the exosomal LMP1 regulated by STIM1 Ca2+ signaling implicated in the remodeling of tumor-associated vasculature through activation of the PI3K/Akt pathway in endothelial cells. In the proposed study, the regulations of delivery of exosomes harboring LMP1 by STIM1 signaling, the activation of PI3K/ Akt pathway in the recipient endothelial cells after the uptake of exosomal LMP1, and the endothelial phenotypes such as proliferation, migration, and permeability are investigated. By utilizing a transgenic zebrafish model established previously, the role of the transfer of exosomal LMP1 in the interaction between NPC and vascular endothelial cells was elucidated at a single-cell level. This study intends to reveal the underlying mechanism through which EBV infection remodels tumor angiogenesis in NPC.