Niclosamide acts as a new inhibitor of vasculogenic mimicry in oral cancer through upregulation of miR-124 and downregulation of STAT3

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.