GOLPH3调控EGFR的内吞降解对胶质瘤增殖作用的研究

表皮生长因子受体（EGFR）的高表达或突变在肿瘤的发生发展中起着重要作用，因而成为重要的肿瘤治疗靶点，但临床上绝大多数患者对靶向EGFR的治疗不敏感，可能与患者个体间伴随着EGFR，高表达或突变的基因差异性较大有关。高尔基蛋白GOLPH3是最新发现的、也是第一个被发现的位于高尔基体的癌基因蛋白，但其作用机制不明。我们发现胶质瘤中GOLPH3表达明显增高，下调GOLPH3可抑制胶质瘤细胞增殖，促进EGFR的内吞降解，并抑制AKT的激活。因此，本项目拟采用培养的细胞、裸鼠肿瘤模型与胶质瘤标本，从分子、细胞与整体水平研究、阐明GOLPH3通过抑制EGFR的内吞降解，激活PI3K-AKT-mTOR信号通路，促进脑胶质瘤生长的机制；并研究GOLPH3是否是伴随着EGFR高表达或突变的基因，为找到适合靶向EGFR治疗的病人提供有益的思路，为脑胶质瘤的分子靶向治疗提供潜在的靶点。

Since the dysregulation of epidermal growth factor receptor (EGFR) induced by its up-regulation or mutation plays a key role in carcinogenesis, EGFR become an important target for cancer molecular treatment. But a large number of cancer patients have not got positive response to the treatment targeting EGFR due to the high variation in gene up-regulation or mutation accompanying EGFR among individuals. GOLPH3 is a brand new and also the first oncogene discovered at Golgi apparatus, but its role and mechanism in carcinogenesis is largely unknown. We found that GOLPH3 was highly expressed in brain glioma tissues. GOLPH3 down-regulation not only inhibited the proliferation of the glioma cells but also promoted the endocytosis and degradation of EGFR. Furthermore, GOLPH3 down-regulation inhibited the activation of AKT, the important molecule in cell proliferation. 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 the endocytosis and degradation of EGFR, activating PI3K-AKT-mTOR signaling pathway at molecular, cellular and whole organism levels. We also determined to exam whether GOLPH3 was a new gene up-regulated or mutated accompanying EGFR in gliomas. Our results will not only identify the mechanism that GOLPH3 promoted the proliferation of tumor cells , but also provide valuable idea for finding patients suitable for treatment targeting EGFR and potential targets for molecular targeting therapy of brain gliomas.