Aberrant ceRNA-mediated regulation of KNG1 contributes to glioblastoma-induced angiogenesis

Abstract

// Yuan Ren 1, 2 , Nan Ji 3 , Xixiong Kang 4 , Renzhi Wang 2 , Wenbin Ma 2 , Zhenjun Hu 4 , Xingfeng Liu 5 , Yajie Wang 1 1 Laboratory of Clinical Medical Research, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China 2 Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China 3 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China 4 Department of Center for Laboratory Diagnosis, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China 5 State Key Laboratory of Biomembrane and Membrane Engineering, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China Correspondence to: Yajie Wang, email: Wangyajie112415@163.com Keywords: glioblastoma, exosome, angiogenesis, kininogen, ceRNA Received: January 26, 2016 Accepted: September 26, 2016 Published: October 14, 2016 ABSTRACT Glioblastoma is a highly vascularized brain tumor that causes high mortality. Kininogen-1 (KNG1) has demonstrated both tumor suppressor and antiangiogenesis properties in gliobastoma cells. We analyzed the microarray and proteomic profiles of tumor tissues from glioblastoma patients (N = 180), and identified potential RNA regulators of the KNG1. Validation experiments in U87 glioblastoma cells showed that the regulation of KNG1 by CTU1, KIAA1274, and RAX was mediated by miR-138. The siRNA-mediated knockdown of CTU1, KIAA1274, or RAX in U87 cells and immortalized human endothelial cells (iHECs) significantly reduced KNG1 expression ( P < 0.05 for all), which resulted in the upregulation of oncogenic EGFR signaling in both cell lines, and stimulated angiogenic processes in cultured iHECs and zebrafish and mouse xenograft models of glioblastoma-induced angiogenesis. Angiogenic transduction of iHECs occurred via the uptake of U87-derived exosomes enriched in miR-138, with the siRNA-mediated knockdown of KNG1, CTU1, KIAA1274, or RAX increasing the level of miR-138 enrichment to varying extents and enhancing the angiogenic effects of the U87-derived exosomes on iHECs. The competing endogenous RNA network of KNG1 represents potential targets for the development of novel therapeutic strategies for glioblastoma.