Niclosamide acts as a new inhibitor of vasculogenic mimicry in oral cancer through upregulation of miR-124 and downregulation of STAT3
Niclosamide acts as a new inhibitor of vasculogenic mimicry in oral cancer through upregulation of miR-124 and downregulation of STAT3
复制标题
Niclosamide 通过上调 miR-124 和下调 STAT3 作为口腔癌血管生成拟态的新型抑制剂
DOI：
10.3892/or.2017.6146
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发表时间：
2018-02-01
期刊：
影响因子：
4.2
通讯作者：
Wang, Yixiang
中科院分区：
文献类型：
--
作者：
Li, Xiaoxu;Yang, Zhicheng;Wang, Yixiang
肿瘤的生长和转移需要营养和氧气。血管生成拟态（vasculogenicmimicry，VM）是近年来发现的一种新的血液供应方式，其特征是肿瘤细胞内形成血管而不是内皮血管。这就是为什么靶向内皮细胞的血管生成剂显示出有限的功效。到目前为止，还没有报道有效的药物用于抑制VM形成。氯硝柳胺是一种用于治疗人类绦虫的口服抗蠕虫药物。最近的研究表明，氯硝柳胺对癌症和其他疾病具有广泛的应用。本研究发现，氯硝柳胺不仅能抑制口腔癌细胞增殖，促进细胞凋亡，而且能通过下调VM相关基因VEGFA、MMP 2、ROCK 1和Cdc 42的表达，抑制VM的形成。此外，氯硝柳胺上调miR-124并下调磷酸化（p）-STAT 3表达。进一步的研究表明，稳定高表达miR-124的细胞系HN 6-miR-124，如氯硝柳胺，可下调p-STAT 3的表达。此外，HN 6-miR-124显示出比对照细胞更低的移动性、侵袭性和VM形成能力。综上所述，我们的研究表明氯硝柳胺通过上调miR-124和下调STAT 3作为口腔癌中VM的新抑制剂发挥作用，为抗VM治疗提供了新的安全的潜在药物候选物。
Tumors require nutrients and oxygen for growth and metastasis. Vasculogenic mimicry (VM) has been found as a new manner of blood supply, which is characterized as the formation of tumor cell-lined vessels instead of endothelial vessels. This is why angiogenesis agents targeted to endothelial cells show a limited efficacy. Up to this point, there is no effective drug reported for inhibiting VM formation. Niclosamide is an oral anti-helminthic drug used to treat human tapeworms. Recent studies have indicated that niclosamide has broad applications for cancer and other diseases. In this study, we found that niclosamide could not only inhibit proliferation and promote apoptosis of oral cancer cells, but also inhibited VM formation in vitro and in vivo through downregulation of the expression of VM-related genes VEGFA, MMP2, ROCK1 and Cdc42. In addition, niclosamide upregulated miR-124 and downregulate phosphorylated (p)-STAT3 expression. Further studies showed that, the stable highly expressing miR-124 cell line HN6-miR-124, such as niclosamide, could downregulate p-STAT3 expression. Moreover, HN6-miR-124 showed lower mobility, invasiveness and VM formation ability than control cells. Taken together, our study suggests that niclosamide functions as a new inhibitor of VM in oral cancer through upregulation of miR-124 and downregulation of STAT3, providing a new and safe potential drug candidate for anti-VM therapy.