Glioma is recognized as a highly angiogenic malignant brain tumor. Vasculogenic mimicry (VM) greatly restricts the therapeutic effect of anti-angiogenic tumor therapy for glioma patients. However, the molecular mechanisms of VM formation in glioma remain unclear. Here, we demonstrated that LINC00339 was upregulated in glioma tissue as well as in glioma cell lines. The expression of LINC00339 in glioma tissues was positively correlated with glioma VM formation. Knockdown of LINC00339 inhibited glioma cell proliferation, migration, invasion, and tube formation, meanwhile downregulating the expression of VM-related molecular MMP-2 and MMP-14. Furthermore, knockdown of LINC00339 significantly increased the expression of miR-539-5p. Both bioinformatics and luciferase reporter assay revealed that LINC00339 regulated the above effects via binding to miR-539-5p. Besides, overexpression of miR-539-5p resulted in decreased expression of TWIST1, a transcription factor known to play an oncogenic role in glioma and identified as a direct target of miR-539-5p. TWIST1 upregulated the promoter activities of MMP-2 and MMP-14. The in vivo study showed that nude mice carrying tumors with knockdown of LINC00339 and overexpression of miR-539-5p exhibited the smallest tumor volume through inhibiting VM formation. In conclusion, LINC00339 may be used as a novel therapeutic target for VM formation in glioma.

胶质瘤被认为是高度血管生成的恶性脑肿瘤。血管生成模拟（VM）极大地限制了抗血管生成肿瘤疗法对神经胶质瘤患者的治疗效果。然而，胶质瘤中VM形成的分子机制仍不清楚。在这里，我们证明了LINC00339在神经胶质瘤组织以及神经胶质瘤细胞系中上调。胶质瘤组织中LINC00339的表达与胶质瘤VM的形成呈正相关。敲低LINC00339可抑制神经胶质瘤细胞的增殖，迁移，侵袭和管形成，同时下调VM相关分子MMP-2和MMP-14的表达。此外，敲低LINC00339显着增加了miR-539-5p的表达。生物信息学和荧光素酶报告基因检测均表明LINC00339通过与miR-539-5p结合来调节上述作用。此外，miR-539-5p的过度表达导致TWIST1的表达降低，TWIST1是已知在神经胶质瘤中起致癌作用并被确定为miR-539-5p的直接靶标的转录因子。TWIST1上调了MMP-2和MMP-14的启动子活性。这体内研究表明，携带带有LINC00339敲低和miR-539-5p过表达的肿瘤的裸鼠通过抑制VM的形成表现出最小的肿瘤体积。总之，LINC00339可用作神经胶质瘤VM形成的新型治疗靶标。