ANKHD1/LINC00346/ZNF655反馈环通过Staufen1介导的mRNA降解在调控胶质瘤血管生成中的作用
Role of ANKHD1/LINC00346/ZNF655 Feedback Loop in Regulating the Glioma Angiogenesis via Staufen1-Mediated mRNA Decay.
作者信息
Yang Chunqing, Zheng Jian, Liu Xiaobai, Xue Yixue, He Qianru, Dong Yiming, Wang Di, Li Zhen, Liu Libo, Ma Jun, Cai Heng, Liu Yunhui
机构信息
Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang 110004, China; Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang 110004, China.
Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110122, China; Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang 110122, China; Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang 110122, China.
出版信息
Mol Ther Nucleic Acids. 2020 Jun 5;20:866-878. doi: 10.1016/j.omtn.2020.05.004. Epub 2020 May 12.
Accumulating evidence shows that long noncoding RNA (lncRNA) dysregulation plays a critical role in tumor angiogenesis. Glioma is characterized by abundant angiogenesis. Herein, we investigated the expression and function of LINC00346 in the regulation of glioma angiogenesis. The present study first demonstrated that ANKHD1 (ankyrin repeat and KH domain-containing protein 1) and LINC00346 were significantly increased in glioma-associated endothelial cells (GECs), whereas ZNF655 (zinc finger protein 655) was decreased in GECs. Meanwhile, ANKHD1 inhibition, LINC00346 inhibition, or ZNF655 overexpression impeded angiogenesis of GECs. Moreover, ANKHD1 targeted LINC00346 and enhanced the stability of LINC00346. In addition, LINC00346 bound to ZNF655 mRNA through their Alu elements so that LINC00346 facilitated the degradation of ZNF655 mRNA via a STAU1 (Staufen1)-mediated mRNA decay (SMD) mechanism. Futhermore, ZNF655 targeted the promoter region of ANKHD1 and formed an ANKHD1/LINC00346/ZNF655 feedback loop that regulated glioma angiogenesis. Finally, knockdown of ANKHD1 and LINC00346, combined with overexpression of ZNF655, resulted in a significant decrease in new vessels and hemoglobin content in vivo. The results identified an ANKHD1/LINC00346/ZNF655 feedback loop in the regulation of glioma angiogenesis that may provide new targets and strategies for targeted therapy against glioma.
越来越多的证据表明，长链非编码RNA（lncRNA）失调在肿瘤血管生成中起关键作用。胶质瘤的特征是丰富的血管生成。在此，我们研究了LINC00346在胶质瘤血管生成调节中的表达和功能。本研究首次证明，锚蛋白重复序列和KH结构域包含蛋白1（ANKHD1）和LINC00346在胶质瘤相关内皮细胞（GECs）中显著增加，而锌指蛋白655（ZNF655）在GECs中减少。同时，ANKHD1抑制、LINC00346抑制或ZNF655过表达会阻碍GECs的血管生成。此外，ANKHD1靶向LINC00346并增强LINC00346的稳定性。另外，LINC00346通过其Alu元件与ZNF655 mRNA结合，从而使LINC00346通过Staufen1介导的mRNA降解（SMD）机制促进ZNF655 mRNA的降解。此外，ZNF655靶向ANKHD1的启动子区域并形成调节胶质瘤血管生成的ANKHD1/LINC00346/ZNF655反馈环。最后，ANKHD1和LINC00346的敲低，联合ZNF655的过表达，导致体内新血管和血红蛋白含量显著降低。这些结果确定了在胶质瘤血管生成调节中的ANKHD1/LINC00346/ZNF655反馈环，这可能为胶质瘤的靶向治疗提供新的靶点和策略。
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