人脑胶质瘤中 RSUME 的 SUMO 化与HIF-1α/VEGF 通路的相关性

摘要

目的：探讨人不同病理级别脑胶质瘤组织中 RWD 结构修饰增强子(RWD containing sumoylation enhancer, RSUME)、泛素样小分子修饰因子(small ubiquitin-like modifier,SUMO)-1、缺氧诱导因子-1α(hypoxia inducible factor-1α)、血管内皮生长因子(VEGF)的表达及其相关性。方法应用 RT-PCR 法检测63例不同级别人脑胶质瘤组织及9例正常脑组织中 RSUME mRNA、HIF-1αmRNA、VEGF mRNA 的表达,免疫组化检测组织中 SUMO-1、HIF-1α、VEGF 表达情况,分析与胶质瘤分级的关系以及表达的相关性。结果脑胶质瘤组织中 RSUME、HIF-1α、VEGF mRNA 较正常脑组织中表达明显增高(P <0.01),并随胶质瘤恶性程度的增高而表达增高(P <0.01),RSUME 与HIF-1α、VEGF 的 mRNA 表达水平呈正相关；脑胶质瘤组织中 SUMO-1、HIF-1α、VEGF 的蛋白表达较正常脑组织明显增高(P <0.01),并随胶质瘤恶性程度的增高而表达增高(P <0.01),SUMO-1与 HIF-1α蛋白表达呈正相关(r =0.857,P <0.01)；Kaplan-Meier 生存分析及 Log-rank 检验显示低表达 RSUME 患者的 PFS 明显长于高表达组(χ2=36.032,P <0.01)。结论RSUME 可能通过 SUMO 化增强 HIF-1α/VEGF 通路表达,预示 RSUME 可能与脑胶质瘤血管新生及肿瘤的侵袭、进展有关,预示 RSUME 可作为胶质瘤治疗的新靶点。%Objective To explore the expressions and correlation of RWD containing sumoylation enhancer (RSUME),small ubiquitin-like modifier (SUMO-1),hypoxia inducible factor-1α(HIF-1α)and vascular endothelial growth factor (VEGF)in gliomas of different pathologic grade.Methods We investigated the expression levels of RSUME mRNA,HIF-1α mRNA and VEGF mRNA with reverse transcription-polymerase chain reaction (RT-PCR),and investigated the immunohistochemical staining to determine the expressions of SUMO-1,HIF-1α and VEGF in 63 cases of human gliomas of different pathologic grade and 9 cases of normal brain tissues.We studied its correlation with the pathologic grade and the relationship between the expression of RSUME promoter sumoylation and HIF-1α/VEGF pathway in gliomas.Results There were significant differences (P <0.01)in the expressions of RSUME mRNA,HIF-1αmRNA and VEGF mRNA in glioma tissues.With the increasing degree of pathologic grade in tumor specimens,the expression levels of RSUME mRNA,HIF-1α mRNA and VEGF mRNA increased markedly (P <0.01 ).There was a positive correlation of the expression levels of RSUME mRNA with HIF-1αmRNA and VEGF mRNA.There were significant differences (P <0.01 )in the expressions of SUMO-1,HIF-1αand VEGF in glioma tissues by immunohistochemical staining.With the ascending of pathologic grade of tumor specimens,the expression levels of SUMO-1,HIF-1α and VEGF increased markedly (P < 0.01 ).There was a positive correlation between the expression level of SUMO-1 and HIF-1α(r =0.857,P <0.01).The Kaplan-Meier analysis and Log-rank test showed significant differences in progress free survival (PFS)between the RSUME high-expression and low-expression groups (χ2 =36.032,P <0.01).Conclusion RSUME may enhance HIF-1α/VEGF pathway through sumoylation in gliomas.It implicates that RSUME is related to angiogenesis in gliomas and can promote tumor invasion and progression,indicating that RSUME can be a novel target in gliomas treatment.