EB病毒转膜蛋白LMP－1通过高表达SDF-1／CXCR7诱导细胞迁移和肿瘤转移

Study on virus-associated cancers has confirmed that viral genes may act as oncogene that interacts with intracellular protein to play important roles in intracellular functions, including the development of cancer. Previous studies have preliminary interpretation of EB virus-associated latent membrane protein (LMP-1) as the oncogene that promotes cell migration and metastasis through the upregulation of SDF-1 and activation of CXR4/7. Results from preliminary experiments have confirmed high expression of LMP-1 and CXCR7 in virus-associated lymphoma and nasopharyngeal carcinoma. On the basis of our study before, we have demonstrated the special roles played by high CXCR7 expression under the activation of SDF-1 activation. Moreover, with its own signaling pathway, the high CXCR7 expression induces cell polarization and migration by activating RAC1 from the Rho family. In this study, we assume LMP-1 may use its unique signaling pathway to regulate the high expression of CXCR7, to activate CXCR7 with high expression, and to enhance the migration activity of tumor cells. Furthermore, since CXCR7 have low expression under physiological conditions, particularly in blood cells, we will use the candidate compounds of inhibition of CXCR7 from preliminary screening, through in vitro and in vivo experiments, to further confirm the unique role of CXCR7 in cell migration. In the meantime, we will screen for compounds to identify the CXCR7 inhibitors that have a particularly affect on tumor metastasis by the suppression of CXCR7.

病毒相关肿瘤的研究已经证实，病毒基因可能作为癌基因通过与细胞内蛋白的相互作用，发挥着重要的功能，包括癌变。既往的研究已经阐释了潜伏状态的EB病毒相关蛋白LMP-1作为癌基因通过上调SDF-1和激活CXCR4／7促进细胞迁移和肿瘤转移。本研究的前期预实验结果已证实了淋巴瘤和鼻咽部癌中LMP－1和CXCR7高表达。相关研究也证实优势表达的CXCR7在SDF-1的激活下发挥着特殊作用，优势表达CXCR7通过激活Rho家族RAC1诱导细胞极化和迁移。在本研究中，我们假设LMP-1可能通过其特有的信号通路，调节新型受体CXCR7的高表达，并可能激活高表达的CXCR7, 持续影响肿瘤细胞的迁移活性。由于CXCR7在多数组织细胞中低表达，本课题将利用初步筛选的特异性阻滞CXCR7活性的一组化合物，进一步证实高表达CXCR7对肿瘤细胞迁移的作用，同时筛选通过抑制CXCR7而影响肿瘤转移的候选化合物。

根据标书科学问题，研究内容和技术路线。首先聚焦探讨EB病毒潜伏状态下CXCR7表达现象的普遍性及肿瘤组织的表达状态。发现肿瘤组织中CXCR7明显高表达，而CXCR4的表达没有明显变化。同时发现EB病毒阳性的肿瘤组织（淋巴瘤，鼻咽癌）和HPV阳性的宫颈癌组织，伴有CXCR7的明显高表达。上述临床结果提示CXCR7具有特殊的生物学意义，且与病毒可能相关。近期研究也揭示CXCR7与血管新生有重要相关性，提示CXCR7在肿瘤形成和生长的相关性。. 在血管生物的在管腔形成实验证实中：用CXCR7激动剂TC14012 激活CXCR7 后，可以直接激活人脐静脉内皮细胞管腔形成，并与TC14012 浓度正相关。此外，基质胶塞实验证实：用CXCL12 激活其受体CXCR7 可以直接诱导小鼠体内管新生（TC14012 是CXCR7 特异性激动剂）。. 在对CXCR7系列研究的基础上，同时专注在血管生物学和血管新生，2017年获得NSFC一项重大研究计划培育项目和一项面上项目持续资助。