GOLPH3调节Wls促进Wnt分泌调控脑胶质瘤增殖的机制研究

多种Wnt蛋白在脑胶质瘤组织中明显升高，且其下游分子β-catenin水平与脑胶质瘤较差预后明显相关，提示Wnt信号通路与脑胶质瘤的发生密切相关。虽然Wnt信号通路已较为清楚，但有关Wnt分泌机制的研究则较少。高尔基蛋白GOLPH3是2009年新发现的、也是第一个被发现的位于高尔基体的癌基因蛋白，我们发现下调GOLPH3可抑制胶质瘤细胞增殖，抑制Wnt分泌的分子伴侣Wls循环转运到高尔基体和细胞膜，促进其在溶酶体降解。是否GOLPH3通过促进Wls的循环转运促进Wnt的分泌导致肿瘤细胞增殖？因此，本项目拟采用培养的胶质瘤U251和U87细胞、裸鼠原位脑胶质瘤模型与胶质瘤标本，从分子、细胞与整体水平研究、阐明GOLPH3通过调节Wls的循环转运调控Wnt的分泌，促进脑胶质瘤生长的机制。预期结果将揭示GOLPH3可能是伴随着Wnt高表达的全新基因，为脑胶质瘤的分子靶向治疗提供潜在的靶点。

Many studies showed that several Wnt proteins were up-regulated in brain gliomas and the level of β-catenin, the main downstream effect molecule of Wnt pathway, is associated with the poor prognosis of patients, suggesting that the close relationship between Wnt pathway and brain gliomas progression. Although the signaling pathways of Wnt proteins are almost clear, the molecular mechanism of Wnt protein secretion is largely unknown. GOLPH3 is a brand new and also the first oncogene at Golgi apparatus discovered in 2009. Previously, we found that GOLPH3 down-regulation decreased the proliferation of glioma cells. Recently, we found that GOLPH3 down-regulation could decrease the protein level of Wls, the chaperon protein of Wnt secretion, and inhibit its being trafficked to Golgi apparatus and plasma membrane. On the contrary, Wls was sorted into the lysosome to be degraded after GOLPH3 down-regulation. Whether GOLPH3 promote glioma cell growth by regulating Wls retrograde trafficking and then Wnt secretion? Thus, by using the cultured glioma cells, nude mice and brain glioma tissues, we intended to study and clarify the mechanism that GOLPH3 promoted glioma growth by regulating Wls retrograde trafficking and Wnt secretion at molecular, cellular and system levels. Our results will not only identify that GOLPH3 may be a new gene up-regulated accompanying Wnt in gliomas, but also provide valuable idea for potential targets for molecular targeting therapy of brain gliomas.