Nan Yang, Guo Hongbao, Guo Liyun, Wang Le, Ren Bingcheng, Yu Kai, Huang Qiang, Zhong Yue
1 Department of Neurosurgery, Tianjin Medical University General Hospital , Tianjin, China .
2 Tianjin Neurological Institute , Tianjin, China .
Hum Gene Ther Clin Dev. 2018 Sep;29(3):156-166. doi: 10.1089/humc.2018.133.
MicroRNAs (miRNAs) are widely expressed and regulate most biological functions. According to several research groups, miR-451 expression is decreased in glioma cells. A previous study also confirmed that miRNA-451 inhibits the PI3K/AKT signaling pathway by directly targeting CAB39, which inhibits glioma cell growth and proliferation and induces apoptosis. However, the specific regulatory mechanism is unclear. Mammalian target of rapamycin (mTOR) is a central regulator of the differentiation, proliferation, and migration of a variety of cells. Hypoxia-inducible factor (HIF)-1α is involved in tumor cell migration and invasion. Close relationships among VEGF overexpression, tumor progression, and poor clinical outcomes have been reported. However, whether miRNA-451 influences glioma cell proliferation and invasion by regulating mTOR, HIF-1α, and VEGF expression remains unknown. This study aimed to assess the effects of miRNA-451 on glioma cell proliferation and invasion in vivo and in vitro by investigating its mechanism. Related gene-protein interactions were also predicted and verified. By targeting CAB39, miRNA-451 likely represses the mTOR/HIF-1α/VEGF pathway to inhibit glioma cell proliferation and invasion. Reverse transcription polymerase chain reaction confirmed that transfection of glioma cells with a lentivirus containing miRNA-451 elevated the expression level of miR-451. Upregulation of miR-451 expression suppressed the growth and invasion of glioma cells in vitro and in vivo by targeting CAB39 and modulating the mTOR/HIF-1α/VEGF signaling pathway. Based on these results, miR-451 suppresses glioma cell proliferation and invasion in vitro and in vivo via suppression of the mTOR/HIF-1α/VEGF signaling pathway by targeting CAB39. Therefore, miR-451 may be a new target for glioma treatment.
微小RNA（miRNA）广泛表达并调节大多数生物学功能。据多个研究小组报道，miR-451在胶质瘤细胞中的表达降低。先前的一项研究还证实，miRNA-451通过直接靶向CAB39抑制PI3K/AKT信号通路，从而抑制胶质瘤细胞的生长和增殖并诱导细胞凋亡。然而，具体的调控机制尚不清楚。雷帕霉素哺乳动物靶蛋白（mTOR）是多种细胞分化、增殖和迁移的核心调节因子。缺氧诱导因子（HIF）-1α参与肿瘤细胞的迁移和侵袭。已有报道称血管内皮生长因子（VEGF）过表达、肿瘤进展与不良临床预后之间存在密切关系。然而，miRNA-451是否通过调节mTOR、HIF-1α和VEGF的表达来影响胶质瘤细胞的增殖和侵袭仍不清楚。本研究旨在通过研究其机制来评估miRNA-451在体内外对胶质瘤细胞增殖和侵袭的影响。还对相关基因-蛋白质相互作用进行了预测和验证。通过靶向CAB39，miRNA-451可能抑制mTOR/HIF-1α/VEGF通路，从而抑制胶质瘤细胞的增殖和侵袭。逆转录聚合酶链反应证实，用含有miRNA-451的慢病毒转染胶质瘤细胞可提高miR-451的表达水平。miR-451表达的上调通过靶向CAB39并调节mTOR/HIF-1α/VEGF信号通路，在体外和体内抑制了胶质瘤细胞的生长和侵袭。基于这些结果，miR-451通过靶向CAB39抑制mTOR/HIF-1α/VEGF信号通路，在体外和体内抑制胶质瘤细胞的增殖和侵袭。因此，miR-451可能是胶质瘤治疗的新靶点。
