关键词： Notch4 VE-Cadherin androgen receptor circRNA7 hepatocellular carcinoma miRNA7-5p vasculogenic mimicry

Mesh ： Antigens, CD / metabolism Biomarkers Cadherins / metabolism Carcinoma, Hepatocellular / etiology metabolism pathology Cell Line, Tumor Gene Expression Regulation, Neoplastic Humans Liver Neoplasms / etiology metabolism pathology MicroRNAs / genetics Neovascularization, Pathologic / genetics metabolism RNA Interference RNA, Circular / genetics Receptor, Notch4 / metabolism Receptors, Androgen / metabolism Signal Transduction

来  源：   DOI：10.1111/jcmm.16022   PDF(Sci-hub)   PDF(Pubmed)

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.
摘要：
雄激素受体（AR）可以在晚期抑制肝细胞癌（HCC）的侵袭和转移。血管生成拟态（VM），一种新的血管化模式，肿瘤组织通过这种模式来滋养自己，与肿瘤进展和转移有关。这里,我们研究了AR在HCC中对VM形成的影响及其机制。结果表明，AR可以下调环状RNA（circRNA）7，上调微小RNA（miRNA）7-5p，并抑制HCC中VM的形成小发夹环R7（ShcircR7）可以逆转对VM的影响，并通过小干扰AR（shAR）增加VE-cadherin和Notch4的表达，而miR-7-5p的抑制阻断VM的形成，并通过AR过表达（oeAR）降低VE-cadherin和Notch4的表达。机制解剖表明，AR可以直接靶向circR7宿主基因启动子来抑制circR7，miR-7-5p可能直接靶向VE-cadherin和Notch43'UTR来抑制其在HCC中的表达。此外,Notch4和/或VE-cadherin的敲低显示shVE-cadherin或shNotch4单独可以部分逆转HCCVM的形成，而shVE-cadherin和shNotch4可以完全抑制HCCVM的形成。这些结果表明，AR可以通过下调HCC中的circRNA7/miRNA7-5p/VE-Cadherin/Notch4信号来抑制HCCVM的形成，这将有助于设计针对HCC的新疗法。
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