Hsc70/β4GalT5复合体在胶质瘤细胞侵袭过程中的调控机制研究

Invasive growth is one of the most important malignant phenotypes in human glioma. Related studies have reported that the glycosylation of integrinβ1 regulated by β4GalT5 plays an essential role in migration and invasion of glioma. Previous studies identified that Hsc70 was interacted with β4GalT5 to form a complex. On the other hand, decreased Hsc70 could suppress glioma cell invasive ability. However, the effect and underlying molecular mechanisms about Hsc70/β4GalT5 complex on glioma cell invasion have still been murky. Thus, research group proposes a hypothesis: Hsc70, which modulates activity of β4GalT5 to regulate the glycosylation of integrinβ1, promotes invasive phenotype of glioma cells and participates the tumorigenesis of glioma. To verify this hypothesis, research group aims to explore the functional role of Hsc70/β4GalT5 complex on glioma cell invasion process, analyze the regulation on glycosylation of integrinβ1, and elucidate the internal molecular mechanisms of related invasion signaling networks in glioma cells and clinical specimens via a series of molecular biology avenues in vitro and in vivo, such as bioinformatics, cell transfection, Lentivirus transfection, co-immunoprecipitation, xenograft, and so on. In summary, the present study focus on investigating the role of Hsc70/β4GalT5 complex in glioma genesis and evaluating the possibility of Hsc70/β4GalT5 to act as a potential target for glioma therapy.

侵袭性生长是脑胶质瘤重要的恶性表型。相关研究已证明β4GalT5介导的β1整合素的糖基化修饰在胶质瘤细胞侵袭过程中起重要作用。课题组预实验发现Hsc70与β4GalT5结合形成复合体，并且下调Hsc70水平可以抑制脑胶质瘤细胞的侵袭能力。由此推测Hsc70通过激活β4GalT5来调节β1整合素的糖基化，进而影响脑胶质瘤细胞的侵袭能力，进一步促进脑胶质瘤的恶性进展。本课题拟通过体内外实验探讨Hsc70/β4GalT5复合体在调控胶质瘤侵袭进程中的重要作用, 阐明Hsc70/β4GalT5复合物形成、功能活化及其调节β1整合素糖基化和下游侵袭相关信号网络的分子机制，并研究靶向Hsc70/β4GalT5复合体治疗的可行性。课题从Hsc70/β4GalT5复合体这个新视点研究脑胶质瘤细胞侵袭能力调控的内在机理，为脑胶质瘤的分子靶向治疗提供新的思路。

胶质瘤是中枢神经系统最常见的恶性肿瘤。蛋白质糖基化修饰在胶质瘤侵袭过程中起重要作用。课题组前期实验发现Hsc70与β4GalT5 结合形成复合体，并且下调Hsc70水平可以抑制脑胶质瘤细胞的侵袭能力。由此推测Hsc70 通过激活β4GalT5来调节β1整合素的糖基化，进而影响脑胶质瘤细胞的侵袭能力。在本项目研究工作中，取得了一系列研究成果：（1）Hsc70在人脑胶质瘤中高表达，且与胶质瘤恶性程度呈正相关；（2）Hsc70通过激活FAK-Src信号通路促进胶质瘤细胞的迁移和侵袭；（3）Hsc70/β4GalT5结合成复合体，通过调节intergrin β1的表达调控人脑胶质瘤的侵袭能力。本研究在工具细胞和胶质瘤细胞中验证Hsc70与β4GalT5结合形成复合体，明确Hsc70在胶质瘤细胞中通过影响β4GalT5的成熟来调节β4GalT5的酶活性及其在催化底物intergrinβ1成熟中的作用，深入分析Hsc70调节β4GalT5的活性对胶质瘤细胞侵袭能力的影响，并对HSC70/β4GalT5复合体对胶质瘤细胞侵袭能力的机制进行深入探讨，为HSC70/β4GalT5复合体作为分子治疗靶点提供依据。