Zhang Xiangyuan, Dong Jiaqiang, He Yan, Zhao Ming, Liu Zhen, Wang Na, Jiang Mingzuo, Zhang Zhe, Liu Gang, Liu Haiming, Nie Yongzhan, Fan Daiming, Tie Jun
State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
Yan'an University, Yan'an 716000, China.
Gene. 2017 Jun 5;615:42-49. doi: 10.1016/j.gene.2017.03.022. Epub 2017 Mar 18.
Aberrant expression of miRNAs is involved in several carcinogenic processes, including tumor growth, metastasis and angiogenesis. The aim of this study was to determine the role of miR-218 in gastric cancer angiogenesis. In situ hybridization was performed on a set of tissue microarray samples to assess the difference in miR-218 expression in vessels between tumor tissues and normal gastric mucosa. In vitro, ectopic expression of miR-218 disturbed the tubular structure and inhibited the migration of endothelial cells. Motility and tube formation were rescued when miR-218 was downregulated. Moreover, miR-218 suppressed endothelial cell sprouting in a fibrin bead sprouting assay. Subsequently, we identified ROBO1 as a target of miR-218 in endothelial cells and determined it was responsible for the effect of miR-218 on tumor angiogenesis. In vivo, local injection of mature miR-218 in xenografted tumors disrupted the vessel plexus and thus inhibited tumor growth. Taken together, our study demonstrated an anti-angiogenic role of miR-218 in gastric cancer and indicated that delivery of miR-218 may be a potential therapeutic strategy to inhibit tumor angiogenesis.
微小RNA（miRNA）的异常表达参与了多种致癌过程，包括肿瘤生长、转移和血管生成。本研究的目的是确定miR-218在胃癌血管生成中的作用。对一组组织微阵列样本进行原位杂交，以评估肿瘤组织和正常胃黏膜血管中miR-218表达的差异。在体外，miR-218的异位表达扰乱了管状结构并抑制了内皮细胞的迁移。当miR-218表达下调时，运动性和管形成得以恢复。此外，在纤维蛋白珠发芽试验中，miR-218抑制了内皮细胞发芽。随后，我们确定ROBO1是内皮细胞中miR-218的靶标，并确定它介导了miR-218对肿瘤血管生成的影响。在体内，在异种移植肿瘤中局部注射成熟的miR-218破坏了血管丛，从而抑制了肿瘤生长。综上所述，我们的研究证明了miR-218在胃癌中的抗血管生成作用，并表明递送miR-218可能是抑制肿瘤血管生成的一种潜在治疗策略。
