Androgen receptor suppresses vasculogenic mimicry in hepatocellular carcinoma via circRNA7/miRNA7-5p/VE-cadherin/Notch4 signalling

Abstract

Androgen receptor (AR) can suppress hepatocellular carcinoma (HCC) invasion and metastasis at an advanced stage. Vasculogenic mimicry (VM), a new vascularization pattern by which tumour tissues nourish themselves, is correlated with tumour progression and metastasis. Here, we investigated the effect of AR on the formation of VM and its mechanism in HCC. The results suggested that AR could down-regulate circular RNA (circRNA) 7, up-regulate micro RNA (miRNA) 7-5p, and suppress the formation of VM in HCC Small hairpin circR7 (ShcircR7) could reverse the impact on VM and expression of VE-cadherin and Notch4 increased by small interfering AR (shAR) in HCC, while inhibition of miR-7-5p blocked the formation of VM and expression of VE-cadherin and Notch4 decreased by AR overexpression (oeAR) in HCC. Mechanism dissection demonstrated that AR could directly target the circR7 host gene promoter to suppress circR7, and miR-7-5p might directly target the VE-cadherin and Notch4 3'UTR to suppress their expression in HCC. In addition, knockdown of Notch4 and/or VE-cadherin revealed that shVE-cadherin or shNotch4 alone could partially reverse the formation of HCC VM, while shVE-cadherin and shNotch4 together could completely suppress the formation of HCC VM. Those results indicate that AR could suppress the formation of HCC VM by down-regulating circRNA7/miRNA7-5p/VE-Cadherin/Notch4 signals in HCC, which will help in the design of novel therapies against HCC.

Keywords: Notch4; VE-Cadherin; androgen receptor; circRNA7; hepatocellular carcinoma; miRNA7-5p; vasculogenic mimicry.