RAD001 targeted HUVECs reverses 12-lipoxygenase-induced angiogenesis in oesophageal squamous cell carcinoma.

12-LOX plays an important role in the progression of various malignancies. However, the underlying mechanisms of the action of 12-LOX and tumour treatment strategies remain not fully defined. In this study, we investigated the possible roles of 12-LOX in ESCC and explored the new therapeutic target. Approximately 73% of ESCC tissues showed marked up-regulation of 12-LOX, which was associated with poor prognosis. 12-LOX overexpression was positively correlated with the malignant progression of ESCC as demonstrated both in vitro and in vivo. Up-regulation of 12-LOX significantly increased the proliferation of ESCC cells and the xenograft volume. Moreover, 12-LOX up-regulation promoted tube formation of HUVECs and tumour angiogenesis in xenografts. Mechanism investigation indicated that 12-LOX overexpression led to activation of the PI3K/AKT/mTOR pathway and the up-regulation of VEGF in ESCC cells. Subsequent analysis indicated that the RAD001 could reverse the 12-LOX-induced promoting effect on ESCC. Specifically, the application of RAD001 inhibited the proliferation of ESCC cells and the tube-forming ability of HUVECs. In the drug group, the xenografts exhibited significant volume reduction and angiogenesis inhibition. We demonstrated that RAD001 could inhibit HUVEC migration. These findings presented the evidence that RAD001 had distinct roles on HUVECs and could exert anti-tumour effects by targeting not only the PI3K/AKT/mTOR pathway but the angiogenesis in ESCC.
(© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)