Overexpression of HOXC10 promotes angiogenesis in human glioma via interaction with PRMT5 and upregulation of VEGFA expression.
Overexpression of HOXC10 promotes angiogenesis in human glioma via interaction with PRMT5 and upregulation of VEGFA expression.
复制标题
HOXC10 的过表达通过与 PRMT5 相互作用和上调 VEGFA 表达促进人胶质瘤中的血管生成
作者：
Tan Z;Chen K;Wu W;Zhou Y;Zhu J;Wu G;Cao L;Zhang X;Guan H;Yang Y;Zhang W;Li J
在胶质瘤患者中，高水平的血管生成与预后不良有关。然而，肿瘤血管生成的分子机制仍不清楚。方法：检测同源盒C10(HOXC10)对人脐静脉内皮细胞(HUVECs)和鸡绒毛膜尿囊膜(CAM)的管形成、迁移和增殖的影响。采用动物异种移植模型，观察HOXC10对异种移植血管生成的影响，以及抗血管内皮生长因子A(VEGFA)的单抗贝伐单抗对HOXC10高表达异种移植瘤的影响。用染色质免疫沉淀法研究HOXC10调控VEGFA表达的机制。结果：高表达HOXC10增强了胶质瘤细胞诱导血管内皮细胞的能力，促进了HUVECs的迁移、增殖和新生血管形成，而沉默HOXC10则相反。我们观察到，在HOXC10过表达的U251 MG细胞形成的肿瘤中，CD31染色显著增加，而在HOXC10沉默的肿瘤中，CD31染色降低。机制上，HOXC10通过与其启动子结合，在转录水平上上调VEGFA的表达。值得注意的是，贝伐单抗，一种抗VEGFA的单抗，显著抑制了HOXC10过表达的肿瘤的生长，并有效地损害了血管生成。蛋白精氨酸甲基转移酶5(PRMT5)和WD重复结构域5(WDR5)是HOXC10介导的VEGFA上调所必需的，它们都是调节组蛋白翻译后修饰所必需的。重要的是，在一组人脑胶质瘤中观察到HOXC10水平和VEGFA表达之间的显著相关性。结论：HOXC10通过转录上调VEGFA的表达诱导胶质瘤血管生成，可能成为抗血管生成治疗的潜在靶点。
High levels of angiogenesis are associated with poor prognosis in patients with gliomas. However, the molecular mechanisms underlying tumor angiogenesis remain unclear. Methods: The effect of homeobox C10 (HOXC10) on tube formation, migration, and proliferation of human umbilical vein endothelial cells (HUVECs) and on chicken chorioallantoic membranes (CAMs) was examined. An animal xenograft model was used to examine the effect of HOXC10 on xenograft angiogenesis or the effect of bevacizumab, a monoclonal antibody against vascular endothelial growth factor A (VEGFA), on HOXC10-overexpressing xenografts. A chromatin immunoprecipitation assay was applied to investigate the mechanism in which HOXC10 regulated VEGFA expression. Results: Overexpressing HOXC10 enhanced the capacity of glioma cells to induce tube formation, migration and proliferation of HUVECs, and neovascularization in CAMs, while silencing HOXC10 had the opposite result. We observed that CD31 staining was significantly increased in tumors formed by HOXC10-overexpressing U251MG cells but reduced in HOXC10-silenced tumors. Mechanistically, HOXC10 could transcriptionally upregulate VEGFA expression by binding to its promoter. Strikingly, treatment with bevacizumab, a monoclonal antibody against VEGFA, significantly inhibited the growth of HOXC10-overexpressing tumors and efficiently impaired angiogenesis. Protein arginine methyltransferase 5 (PRMT5) and WD repeat domain 5 (WDR5), both of which regulate histone post-translational modifications, were required for HOXC10-mediated VEGFA upregulation. Importantly, a significant correlation between HOXC10 levels and VEGFA expression was observed in a cohort of human gliomas. Conclusions: This study suggests that HOXC10 induces glioma angiogenesis by transcriptionally upregulating VEGFA expression, and may represent a potential target for antiangiogenic therapy in gliomas.