School of Life Sciences, Anhui Medical University, Hefei, China.
Departments of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, China.
J Cell Mol Med. 2020 Dec;24(23):14110-14120. doi: 10.1111/jcmm.16022. Epub 2020 Oct 28.
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.
雄激素受体（AR）可在晚期抑制肝细胞癌（HCC）的侵袭和转移。血管生成拟态（VM）是一种新的血管生成模式，肿瘤组织通过该模式为自身提供营养，与肿瘤的进展和转移相关。在此，我们研究了 AR 对 HCC 中 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 microRNA（miRNA）7-5p，抑制 HCC 中 VM 的形成。小发夹 circR7（ShcircR7）可以逆转 AR 沉默（shAR）对 HCC 中 VM 形成和 VE-钙粘蛋白和 Notch4 表达的影响，而 miR-7-5p 的抑制则阻断了由 AR 过表达（oeAR）在 HCC 中降低的 VM 形成和 VE-钙粘蛋白和 Notch4 的表达。机制分析表明，AR 可以直接靶向 circR7 宿主基因启动子抑制 circR7，而 miR-7-5p 可能直接靶向 VE-钙粘蛋白和 Notch4 的 3'UTR 抑制它们在 HCC 中的表达。此外，敲低 Notch4 和/或 VE-钙粘蛋白表明，单独敲低 shVE-cadherin 或 shNotch4 可以部分逆转 HCC VM 的形成，而同时敲低 shVE-cadherin 和 shNotch4 则可以完全抑制 HCC VM 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 HCC 的形成，这有助于设计针对 HCC 的新治疗方法。
