title: Combination of Endothelial-Monocyte-Activating Polypeptide-II with Temozolomide Suppress Malignant Biological Behaviors of Human Glioblastoma Stem Cells via miR-590-3p/MACC1 Inhibiting PI3K/AKT/mTOR Signal Pathway.
abstract: This study aims to investigate the effect of Endothelial-Monocyte-Activating Polypeptide-II (EMAP-II) combined with temozolomide (TMZ) upon glioblastoma stem cells (GSCs) and its possible molecular mechanisms. In this study, combination of EMAP-II with TMZ inhibited cell viability, migration and invasion in GSCs, and autophagy inhibitor 3-methyl adenine (3-MA) and chloroquine (CQ) partly reverse the anti-proliferative effect of the combination treatment. Autophagic vacuoles were formed in GSCs after the combination therapy, accompanied with the up-regulation of LC3-II and Beclin-1 as well as the down-regulation of p62/SQSTM1. Further, miR-590-3p was up-regulated and Metastasis-associated in colon cancer 1 (MACC1) was down-regulated by the combination treatment in GSCs; MiR-590-3p overexpression and MACC1 knockdown up-regulated LC3-II and Beclin-1 as well as down-regulated p62/SQSTM1 in GSCs; MACC1 was identified as a direct target of miR-590-3p, mediating the effects of miR-590-3p in the combination treatment. Furthermore, the combination treatment and MACC1 knockdown decreased p-PI3K, p-Akt, p-mTOR, p-S6 and p-4EBP in GSCs; PI3K/Akt agonist insulin-like growth factor-1(IGF-1) partly blocked the effect of the combination treatment. Moreover,in vivoxenograft models, the mice given stable overexpressed miR-590-3p cells and treated with EMAP-II and TMZ had the smallest tumor sizes, besides, miR-590-3p + EMAP-II + TMZ up-regulated the expression level of miR-590-3p, LC3-II and Beclin-1 as well as down-regulated p62/SQSTM1. In conclusion, these results elucidated anovel molecular mechanism of EMAP-II in combination with TMZ suppressed malignant biological behaviors of GSCs via miR-590-3p/MACC1 inhibiting PI3K/AKT/mTOR signaling pathway, and might provide potential therapeutic approaches for human GSCs.
authors.affiliation: Department of Neurosurgery, Shengjing Hospital of China Medical UniversityShenyang, China; Liaoning Research Center for Translational Medicine in Nervous System DiseaseShenyang, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical UniversityShenyang, China; Key Laboratory of Cell Biology, Ministry of Public Health of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical UniversityShenyang, China.
authors.forename: Libo
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical UniversityShenyang, China; Key Laboratory of Cell Biology, Ministry of Public Health of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical UniversityShenyang, China.
authors.forename: Yixue
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Department of Neurosurgery, Shengjing Hospital of China Medical UniversityShenyang, China; Liaoning Research Center for Translational Medicine in Nervous System DiseaseShenyang, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Neurosurgery, Shengjing Hospital of China Medical UniversityShenyang, China; Liaoning Research Center for Translational Medicine in Nervous System DiseaseShenyang, China.
authors.forename: Xiaobai
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical UniversityShenyang, China; Key Laboratory of Cell Biology, Ministry of Public Health of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical UniversityShenyang, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Neurosurgery, Shengjing Hospital of China Medical UniversityShenyang, China; Liaoning Research Center for Translational Medicine in Nervous System DiseaseShenyang, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Shengjing Hospital of China Medical UniversityShenyang, China; Liaoning Research Center for Translational Medicine in Nervous System DiseaseShenyang, China.
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Liu
keywords: EMAP-II; GSCs; MACC1; MiR-590-3p; TMZ; autophagy; microRNAs