HMGB1-RAGE激活STAT3信号通路从而抑制小胶质细胞（MG）免疫活性的机制研究

Microglia (MG) have been shown to play an important role in tumorigenesis and glioma development, however the exact mechanism remains unknown. Signal transduction and transcriptional activation factor 3 (STAT3) pathways may promote tumor growth via inhibition the activity of MG. Our previous study has been shown that the immune function of MG could be partially reduced by the receptor of advanced glycosylation end products (RAGE) through the STAT3 pathway, however, the exact mechanism is unclear. Our preliminary data showed that the high mobility group box 1 (HMGB1) was highly expressed in the microenvironment of glioma, which up-regulated RAGE expression of MG in the medium containing HMGB1. In addition, we also observed that the blockage of RAGE pathway may partially repress the activation of STAT3 pathway. We therefore hypothesize that the binding between HMGB1 and RAGE may increase the RAGE expression and thereby the activated RAGE pathway could activate the STAT3 pathway, which in turn inhibit the immune function of MG. This hypothesis may be a mechanism of immune escape of glioma from MG. In the present study, we will prove our hypothesis using intracranial glioma model in mice from tissue-cell-molecule levels by siRNA, living imaging technology, Co-Immunoprecipitation assay and so on. This research will provide a potential target as well as a new method for the immune therapy in glioma.

小胶质细胞（MG）在胶质瘤的发展中发挥重要作用，但是具体机制不详。信号转导及转录活化因子3（STAT3）可以抑制小胶质细胞的活性从而促进肿瘤生长。本课题组已证实，晚期糖基化终末产物受体（RAGE）可以作用于STAT3信号通路从而影响小胶质细胞的免疫功能，但是具体调控机制不详。在预实验中，我们发现：高迁移率族蛋白1（HMGB1）在胶质瘤微环境中呈现高表达，并且可以引起小胶质细胞中RAGE的上调。不仅如此，阻断RAGE信号通路后可以部分抑制STAT3的表达。因此，我们推测“HMGB1与RAGE结合后可以上调RAGE的表达，并通过RAGE信号通路进一步激活STAT3信号通路，从而抑制小胶质细胞的免疫活性”是胶质瘤免疫逃逸的新的重要机制。我们拟制备胶质瘤小鼠模型，应用siRNA，活体成像，免疫共沉淀等技术，从组织-细胞-分子层面证明我们的假设，此研究将为胶质瘤的免疫治疗提供新思路和新靶点。

结题摘要.胶质瘤（Glioma）是成人神经系统中最常见的原发性恶性肿瘤，肿瘤进展快，预后很差。先前的研究提示胶质瘤微环境中有HMGB1表达。我们近期也发现在胶质瘤患者肿瘤周围的细胞外液中可以检测到HMGB1。因此，HMGB1极有可能激活小胶质细胞（MG/MP），从而抑制胶质瘤生长的重要因素。我们的研究发现，HMGB1不仅在胶质瘤细胞株中广泛表达，在动物和人类胶质瘤中也大量存在。进一步的实验证实，HMGB1可以通过RAGE-STAT3信号通路抑制小胶质细胞的活性，从而促进胶质瘤的发生发展，不仅如此，HMGB1还可以部分通过β-catenin/TCF4信号通路影响胶质瘤的预后。.本课题在先前的基础上，进一步探讨了胶质瘤微环境中，免疫细胞被激活的可能机制，以及多种信号通路之间的相关性。为今后在胶质瘤的生物免疫学治疗中提供了新思路与新靶点。