Role of ANKHD1/LINC00346/ZNF655 Feedback Loop in Regulating the Glioma Angiogenesis via Staufen1-Mediated mRNA Decay

Abstract

Accumulating evidence shows that long non-coding RNAs (lncRNAs) dysregulation plays a critical role in tumor angiogenesis. Glioma is characterized by angiogenesis. Herein, we investigated the expression and function of LINC00346 in the regulation of glioma angiogenesis. The present study first demonstrated that ANKHD1 was significantly increased in glioma-associated endothelial cells (GECs) and facilitated angiogenesis of GECs. LncRNA microarray analysis was conducted to identify the differentially expressed LINC00346 in GECs treated with sh-ANKHD1. We verified that LINC00346 was increased in GECs and then the mRNA microarray data indicated the differentially expressed ZNF655 in GECs treated with sh-LINC00346. Further we demonstrated that ZNF655 was reduced in GECs. Meanwhile, LINC00346 inhibition or ZNF655 overexpression impeded angiogenesis of GECs. Moreover, ANKHD1 targeted LINC00346 and enhanced LINC00346's stability. In addition, LINC00346 bound to ZNF655 mRNA through their Alu elements so that LINC00346 facilitated the degradation of ZNF655 mRNA via STAU1-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 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. Funding Statement: This work is supported by grants from the Natural Science Foundation of China (81672511 and 81573010), Liaoning Science and Technology Plan Project (No. 2017225020, 2015225007), Project of Key Laboratory of Neuro-oncology in Liaoning Province (112-2400017005), special developmental project guided by central government of Liaoning Province (No. 2017011553-301) and outstanding scientific fund of Shengjing hospital (No. 201304). Declaration of Interests: We declare that all the authors have no conflict of interest in relation to the work described. Ethics Approval Statement: Not required.