Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hankou, Wuhan, 430030, Hubei, PR China.
Department of Ultrasound, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hankou, Wuhan, 430030, Hubei, PR China.
Exp Cell Res. 2021 Nov 15;408(2):112804. doi: 10.1016/j.yexcr.2021.112804. Epub 2021 Sep 3.
Angiogenesis has been certified to account for tumor pathobiology. Circular RNAs (circRNAs) have been demonstrated to be involved in angiogenesis-related diseases, including hepatocellular carcinoma (HCC). Nevertheless, the regulatory roles of most circRNAs remain obscure. This study aims to uncover the function of hsa_circ_0004018 on angiogenesis in HCC. Firstly, quantitative real-time RT-PCR (RT-qPCR) analyzed that circ_0004018 was definitely down-regulated in HCC. Western blot analysis was conducted to detect the protein level of fused protein in sarcoma (FUS) and TIMP metallopeptidase inhibitor 2 (TIMP2). Functional assays were carried out to assess the impacts of circ_0004018 on HCC. From the experimental results, we found that overexpression of circ_0004018 significantly inhibited angiogenesis in HCC. The regulatory mechanism of circ_0004018 in HCC was determined by chromatin immunoprecipitation (ChIP), luciferase reporter assays and RNA immunoprecipitation (RIP) assay. Therefore, we proved that estrogen receptor 1 (ESR1) mediated circ_0004018 regulated TIMP2 by recruiting FUS. A series of rescue assays verified that circ_0004018 participated in angiogenesis in HCC via modulating TIMP2. In summary, this paper disclosed that ESR1 activated circ_0004018 inhibited angiogenesis in HCC via binding to FUS and stabilizing TIMP2 expression.
血管生成已被证实与肿瘤病理生物学有关。环状 RNA（circRNAs）已被证明参与血管生成相关疾病，包括肝细胞癌（HCC）。然而，大多数 circRNAs 的调节作用仍不清楚。本研究旨在揭示 hsa_circ_0004018 在 HCC 血管生成中的功能。首先，定量实时 RT-PCR（RT-qPCR）分析表明 circ_0004018 在 HCC 中明显下调。进行 Western blot 分析以检测肉瘤融合蛋白（FUS）和 TIMP 金属蛋白酶抑制剂 2（TIMP2）的蛋白水平。进行功能测定以评估 circ_0004018 对 HCC 的影响。从实验结果中，我们发现 circ_0004018 的过表达显著抑制了 HCC 的血管生成。circ_0004018 在 HCC 中的调节机制通过染色质免疫沉淀（ChIP）、荧光素酶报告基因测定和 RNA 免疫沉淀（RIP）测定来确定。因此，我们证明雌激素受体 1（ESR1）通过募集 FUS 介导 circ_0004018 调节 TIMP2。一系列挽救实验验证了 circ_0004018 通过调节 TIMP2 参与 HCC 中的血管生成。总之，本文揭示了 ESR1 激活 circ_0004018 通过与 FUS 结合并稳定 TIMP2 表达来抑制 HCC 中的血管生成。
