Human malignant gliomas are the most common and aggressive primary malignant tumors of the human central nervous system. Vasculogenic mimicry (VM), which refers to the formation of a tumor blood supply system independently of endothelial cells, contributes to the malignant progression of glioma. Therefore, VM is considered a potential target for glioma therapy. Accumulated evidence indicates that alterations in SUMOylation, a reversible post-translational modification, are involved in tumorigenesis and progression. In the present study, we found that UBA2 and RALY were upregulated in glioma tissues and cell lines. Downregulation of UBA2 and RALY inhibited the migration, invasion, and VM of glioma cells. RALY can be SUMOylated by conjugation with SUMO1, which is facilitated by the overexpression of UBA2. The SUMOylation of RALY increases its stability, which in turn increases its expression as well as its promoting effect on FOXD1 mRNA. The overexpression of FOXD1 promotes DKK1 transcription by activating its promoter, thereby promoting glioma cell migration, invasion, and VM. Remarkably, the combined knockdown of UBA2, RALY, and FOXD1 resulted in the smallest tumor volumes and the longest survivals of nude mice in vivo. UBA2/RALY/FOXD1/DKK1 axis may play crucial roles in regulating VM in glioma, which may contribute to the development of potential strategies for the treatment of gliomas.

人类恶性胶质瘤是人类中枢神经系统最常见和最具侵袭性的原发性恶性肿瘤。血管生成拟态（VM）是指独立于内皮细胞形成肿瘤血液供应系统，有助于神经胶质瘤的恶性进展。因此，VM被认为是神经胶质瘤治疗的潜在靶点。积累的证据表明，SUMO 化（一种可逆的翻译后修饰）的改变与肿瘤的发生和进展有关。在本研究中，我们发现 UBA2 和 RALY 在神经胶质瘤组织和细胞系中表达上调。UBA2和RALY的下调抑制了胶质瘤细胞的迁移、侵袭和VM。RALY 可以通过与 SUMO1 结合而被 SUMO 化，而 UBA2 的过度表达会促进这种作用。RALY 的 SUMO 化增加了其稳定性，从而增加了其表达以及对 FOXD1 mRNA 的促进作用。FOXD1的过表达通过激活其启动子促进DKK1转录，从而促进胶质瘤细胞迁移、侵袭和VM。值得注意的是，UBA2、RALY 和 FOXD1 的联合敲除导致裸鼠体内肿瘤体积最小和存活时间最长。UBA2/RALY/FOXD1/DKK1轴可能在调节神经胶质瘤VM中发挥关键作用，这可能有助于开发神经胶质瘤治疗的潜在策略。