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.

Keywords: HOXC10, glioma, angiogenesis, VEGFA, bevacizumab

高水平的血管生成与神经胶质瘤患者的不良预后有关。但是，尚不清楚肿瘤血管生成的分子机制。

方法：检测同源盒C10（HOXC10）对人脐静脉内皮细胞（HUVEC）的管形成，迁移和增殖以及鸡绒膜尿囊膜（CAM）的影响。动物异种移植模型用于检查HOXC10对异种移植血管生成的影响或贝伐单抗（一种抗血管内皮生长因子A（VEGFA）的单克隆抗体）对过表达HOXC10的异种移植的影响。染色质免疫沉淀法用于研究HOXC10调节VEGFA表达的机制。

结果：过表达HOXC10增强了胶质瘤细胞诱导CAM的管形成，HUVEC迁移和增殖以及CAM中新血管形成的能力，而沉默HOXC10却产生了相反的结果。我们观察到，CD31染色在过表达HOXC10的U251MG细胞形成的肿瘤中显着增加，而在HOXC10沉默的肿瘤中减少。从机理上讲，HOXC10可以通过与其启动子结合而在转录上上调VEGFA的表达。令人惊讶的是，用贝伐单抗（一种针对VEGFA的单克隆抗体）治疗可显着抑制过表达HOXC10的肿瘤的生长，并有效地削弱了血管生成。HOXC10介导的VEGFA上调需要蛋白精氨酸甲基转移酶5（PRMT5）和WD重复结构域5（WDR5），两者均调节组蛋白的翻译后修饰。重要的，

结论：这项研究表明，HOXC10通过转录上调VEGFA的表达来诱导神经胶质瘤的血管生成，并且可能代表神经胶质瘤的抗血管生成治疗的潜在靶标。

关键词：HOXC10，神经胶质瘤，血管生成，VEGFA，贝伐单抗