Distinctive role of vasohibin-1A and its splicing variant vasohibin-1B in tumor angiogenesis
Distinctive role of vasohibin-1A and its splicing variant vasohibin-1B in tumor angiogenesis
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DOI：
10.1038/cgt.2016.13
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发表时间：
2016-05-01
影响因子：
6.4
通讯作者：
Sato, Y.
中科院分区：
文献类型：
--
作者：
Horie, S.;Suzuki, Y.;Sato, Y.
Vasohibin-1 (VASH1) 被分离为内皮细胞 (EC) 中表达的血管生成的负反馈调节因子。 VASH1有两个转录本，即由7个外显子组成的全长VASH1A和由4个外显子组成的剪接变体VASH1B。在这里，我们比较了 VASH1A 和 VASH1B 对肿瘤血管生成的影响。当 EC 转染 VASH1A 或 VASH1B cDNA 时，VASH1B 转染子而非 VASH1A 转染子诱导 EC 的自噬性细胞死亡。通过声孔法，将VASH1A或VASH1B基因特异性转染至小鼠肿瘤血管的EC中。-VASH1A和VASH1B均降低肿瘤血管密度并抑制肿瘤生长。 VASH1A使剩余肿瘤血管正常化，增加其灌注率，减少肿瘤缺氧并增强抗癌化疗疗效，而VASH1B修剪肿瘤血管但不引起正常化，增加肿瘤缺氧和肿瘤坏死，并且不增强抗癌化疗疗效。交替转染 VASH1A 和 VASH1B 基因的小鼠显示出抗肿瘤活性和肿瘤血管正常化的最高效果。我们目前对 VASH1A 和 VASH1B 的研究结果应该提供一种创新方法，通过平衡血管正常化和修剪来提高抗血管生成癌症治疗的功效。
Vasohibin-1 (VASH1) was isolated as a negative-feedback regulator of angiogenesis expressed in endothelial cells (ECs). There are two transcripts of VASH1, that is, the full-length VASH1A consisting of seven exons and the splicing variant VASH1B consisting of four exons. Here, we compared the effects of VASH1A and VASH1B on tumor angiogenesis. When ECs were transfected with VASH1A or VASH1B cDNAs, VASH1B transfectants, but not VASH1A Ones, induced autophagic cell death of ECs. With sonoporation, the VASH1A or VASH1B gene were transfected specifically in ECs of tumor vessels in mice.-Both VASH1A and VASH1B decreased tumor vessel density and inhibited tumor growth. VASH1A normalized the remaining tumor vessels, increased their rate of perfusion, decreased tumor hypoxia and enhanced the efficacy of anticancer chemotherapy, whereas VASH1B pruned tumor vessels without causing normalization, increased tumor hypoxia and tumor necrosis and did not enhance the efficacy of anticancer chemotherapy. The alternate transfection of mice with the VASH1A and VASH1B gene showed the highest effects on antitumor activity and normalization of tumor vessels. Our present findings on VASH1A and VASH1B should provide an innovative approach that would improve the efficacy of antiangiogenic cancer therapy by balancing vascular normalization and pruning.