Tumor Suppressor microRNA-138 Suppresses Low-Grade Glioma Development and Metastasis via Regulating IGF2BP2

Yang Yang,1,2,* Xinyu Liu,3,* Lulu Cheng,2 Li Li,2 Zhenyu Wei,4 Zong Wang,2 Gang Han,2 Xuefeng Wan,2 Zaizhong Wang,2 Jianhua Zhang,5 Chuanliang Chen1 1Henan Key Laboratory for Medical Imaging of Neurological Diseases, People’s Hospital of Zhengzhou University, Zhengzhou 450003, People’s Republic of China; 2Department of Neurosurgery, Zhumadian Central Hospital, Zhumadian 463000, People’s Republic of China; 3School of Intelligent Manufacturing, The Huanghuai University, Zhumadian 463000, People’s Republic of China; 4Department of Neurosurgery, Second Affiliated Hospital of Xinxiang Medical College, Xinxiang 453000, People’s Republic of China; 5Medical Engineering Technology and Data Mining Institute of Zhengzhou University, Zhengzhou 450000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chuanliang ChenHenan Key Laboratory for Medical Imaging of Neurological Diseases, People’s Hospital of Zhengzhou University, Zhengzhou 450003, People’s Republic of ChinaEmail chenchuanliangsy@126.comBackground: Low-grade gliomas (LGG), approximately constitute one-third of all types of gliomas, are prone to relapse and metastasis. MicroRNA-138 (miR-138) is reported to be dysregulated in diverse human tumors and mainly function as a tumor suppressor. In this study, we analyzed the expression profile and function of miR-138 in LGG.Methods: Quantitative PCR (qPCR) and public database bioinformatics analysis were performed to determine the miR-138 levels in LGG. MiR-138 overexpression in LGG cells was achieved by miR-138 mimics transfection. Cell proliferation was assessed by CCK8, EdU and colony formation assays. Cell invasion and migration were analyzed by transwell and wound-healing assays. Xenograft model was employed to study the role of miR-138 in LGG growth in vivo. The target of miR-138 was validated by multiple methods, such as luciferase reporter assay, RT-qPCR and Western blot. Bioinformatics analysis was conducted to explore the molecular mechanisms by which miR-138 contributed to LGG progression.Results: miR-138 was significantly downregulated in LGG tumor tissues and low expression of miR-138 was significantly associated with poor prognosis as well as relapse and metastasis in LGG patients. Functional analysis indicated that ectopic miR-138 expression suppressed LGG cell growth and invasive phenotype in vitro, and inhibited tumor development in vivo. Moreover, miR-138 directly targeted and repressed insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) by targeting the 3ʹ-UTR of IGF2BP2, inhibiting epithelial to mesenchymal transition (EMT) to attenuate LGG aggressiveness. In addition, we found that elevated IGF2BP2 expression correlates with poor survival of LGG patients.Conclusion: miR-138 may function as a tumor inhibitor by directly inhibiting IGF2BP2 and suppressing EMT in the progression of LGG.Keywords: miR-138, tumor prognosis, LGG, IGF2BP2, EMT