转录因子JunD的SUMO化修饰与胶质瘤高度侵袭的关系

The highly invasion of glioma is an important symbol of malignant transformation, which results in poor prognosis, high recurrence rate and high mortality rate. At present, the molecular mechanisms of glioma invasion are largely unknown. As product of proto-oncogene junD, transcription factor JunD activates the expressions of MMP13 (matrix metallopeptidase 13) and C4.4A (homologue of the urokinase receptor), while MMP and urokinase facilitate invasion and metastasis in several kinds of tumor. Lately, we found SUMOylation sites in JunD protein sequence, whereas SUMOylation mainly functions in transcriptional regulation. Up to the present, there is no report on JunD function in glioma invasion. Accordingly, we hypothesize that JunD plays an important role in the course of glioma invasion, which could be regulated by SUMOylation. In this project, we intend to analyze the interaction between JunD and SUMO, and analyze the transcriptional regulation of SUMOylation on JunD. By means of RNA interference and mutant JunD, the impact of SUMOylation of JunD on glioma invasion will be elucidated. The study will identify functions of JunD during glioma invasion, and the influence of SUMOylation on JunD function. From the new perspective of SUMOylation, the project is expected to lay the foundation for revealing the mechanism of glioma invasion, as well as provide new ideas for the targeted therapy of malignant glioma.

胶质瘤高度侵袭是其恶性转化的重要标志，导致患者预后极差，并且复发率高、死亡率高。当前，对于胶质瘤发生及侵袭的分子机制尚不明确。原癌基因junD表达的转录因子(JunD)能够激活MMP13和C4.4A（尿激酶受体类似物）的表达，MMP和尿激酶作为蛋白水解酶，可促进多种肿瘤细胞的侵袭转移。同时，课题组发现JunD蛋白序列中存在SUMO化位点，而SUMO化修饰的一大功能就是调控转录。目前尚无JunD在胶质瘤侵袭行为中的功能报道。据此我们提出假设，JunD在胶质瘤侵袭过程中发挥重要功能，此功能受SUMO化修饰调控。本课题拟检测JunD和SUMO的相互作用，分析SUMO化修饰对JunD转录活性的调控；利用过表达及JunD突变体等手段，鉴定JunD的SUMO化对胶质瘤侵袭能力的影响。本研究可望从SUMO化修饰这个新视点，为揭示胶质瘤侵袭机制奠定基础，并为恶性胶质瘤的靶向治疗提供新的思路。

胶质瘤高度侵袭是其恶性转化的重要标志，导致患者预后极差，并且复发率高、死亡率高。当前，对于胶质瘤发生及侵袭的分子机制尚不明确。原癌基因junD表达的转录因子(JunD)能够激活MMP13和C4.4A（尿激酶受体类似物）的表达，MMP和尿激酶作为蛋白水解酶，可促进多种肿瘤细胞的侵袭转移。课题组研究证实发现胶质瘤细胞内源的JunD蛋白可发生SUMO化修饰，而SUMO化修饰的一大功能就是调控转录。因此我们研究了JunD蛋白在胶质瘤侵袭行为中的功能，发现JunD在胶质瘤侵袭过程中发挥重要功能，此功能受SUMO化修饰调控。本课题检测了JunD和SUMO的相互作用，分析SUMO化修饰对JunD转录活性的调控；同时利用过表达及JunD突变体等手段，鉴定JunD的SUMO化对胶质瘤侵袭能力的影响。本研究可望从SUMO化修饰这个新视点，为揭示胶质瘤侵袭机制奠定基础，并为恶性胶质瘤的靶向治疗提供新的思路。