Department of Cardiothoracic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210000, China.
Department of Cardiothoracic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210000, China; Department of Cardiothoracic Surgery, Jinling Hospital, Southeast University, Nanjing, 210000, China.
Biochem Biophys Res Commun. 2020 Jun 25;527(2):545-552. doi: 10.1016/j.bbrc.2020.04.108. Epub 2020 May 15.
Angiogenesis is a core hallmark of advanced cancers, especially in lung adenocarcinoma (LUAD). However, the underlying functions and mechanisms of lncRNAs in tumor angiogenesis remain largely unknown. Here we found that linc00665 depletion could markedly depressed proliferation and capillary tube formation of HUVECs in vitro. Mechanistically, linc00665 directly interacted with YB-1 protein, enhanced its stability through inhibiting ubiquitination-dependent proteolysis and stimulated its nuclear translocation in LUAD cells. The accumulated nuclear YB-1 activated expression of ANGPT4, ANGPTL3 and VEGFA by binding to their promoters, contributing to tumor-related angiogenesis in vitro and in vivo. Collectively, we conclude that linc00665 induces tumor-related angiogenesis in LUAD by directly interacting with YB-1 and activating YB-1-ANGPT4/ANGPTL3/VEGFA axis, which provides promising anti-angiogenic targets for cancer therapy.
血管生成是晚期癌症的核心标志，尤其是在肺腺癌 (LUAD) 中。然而，lncRNAs 在肿瘤血管生成中的潜在功能和机制在很大程度上仍然未知。在这里，我们发现 linc00665 的缺失可显著抑制 HUVECs 的体外增殖和毛细血管形成。在机制上，linc00665 可直接与 YB-1 蛋白相互作用，通过抑制泛素化依赖性蛋白水解来增强其稳定性，并刺激其在 LUAD 细胞中的核转位。核内积累的 YB-1 通过与启动子结合来激活 ANGPT4、ANGPTL3 和 VEGFA 的表达，从而促进体外和体内与肿瘤相关的血管生成。总之，我们的研究结果表明，linc00665 通过与 YB-1 直接相互作用并激活 YB-1-ANGPT4/ANGPTL3/VEGFA 轴，诱导 LUAD 中的肿瘤相关血管生成，为癌症治疗提供了有前途的抗血管生成靶点。
