Downregulation of miR-137 and miR-6500-3p promotes cell proliferation in pediatric high-grade gliomas.

// Muh-Lii Liang 1,2,* , Tsung-Han Hsieh 3,4,* , Kim-Hai Ng 5 , Ya-Ni Tsai 5 , Cheng-Fong Tsai 6 , Meng-En Chao 7,8 , Da-Jung Liu 2 , Shing-Shiung Chu 7,8 , Wan Chen 7,8 , Yun-Ru Liu 4,9 , Ren-Shyan Liu 10,11,12 , Shih-Chieh Lin 13 , Donald Ming-Tak Ho 10,13 , Tai-Tong Wong 2,7,8,9 , Muh-Hwa Yang 1,14,15,16,17 and Hsei-Wei Wang 1,5,6,14 1 Institutes of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan 2 Division of Pediatric Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan 3 PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan 4 Comprehensive Cancer Center of Taipei Medical University, Taipei Medical University, Taipei, Taiwan 5 Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan 6 Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan 7 Institutes of Clinical Medicine, Taipei Medical University, Taipei, Taiwan 8 Department of Neurosurgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan 9 Joint Biobank, Office of Human Research, Taipei Medical University, Taipei, Taiwan 10 School of Medicine, National Yang-Ming University, Taipei, Taiwan 11 National PET/Cyclotron Center, Department of Nuclear Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 12 Molecular and Genetic Imaging Core/Taiwan Mouse Clinic National Comprehensive Mouse Phenotyping and Drug Testing Center, Taipei, Taiwan 13 Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 14 Cancer Research Center & Genome Research Center, National Yang-Ming University, Taipei, Taiwan 15 Division of Hematology-Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 16 Immunity and Inflammation Research Center, National Yang-Ming University, Taipei, Taiwan 17 Genomic Research Center, Academia Sinica, Taipei, Taiwan * These authors have contributed equally to this work Correspondence to: Muh-Hwa Yang, email: // Tai-Tong Wong, email: // Keywords : miR-137, miR-6500-3p, CENPE, KIF14, NCAPG Received : December 15, 2015 Accepted : February 18, 2016 Published : February 25, 2016 Abstract Pediatric high-grade gliomas (pHGGs) are aggressive brain tumors affecting children, and outcomes have remained dismal, even with access to new multimodal therapies. In this study, we compared the miRNomes and transcriptomes of pediatric low- (pLGGs) and high-grade gliomas (pHGGs) using small RNA sequencing (smRNA-Seq) and gene expression microarray, respectively. Through integrated bioinformatics analyses and experimental validation, we identified miR-137 and miR-6500-3p as significantly downregulated in pHGGs. miR-137 or miR-6500-3p overexpression reduced cell proliferation in two pHGG cell lines, SF188 and UW479. CENPE, KIF14 and NCAPG levels were significantly higher in pHGGs than pLGGs, and were direct targets of miR-137 or miR-6500-3p. Furthermore, knockdown of CENPE, KIF14 or NCAPG combined with temozolomide treatment resulted in a combined suppressive effect on pHGG cell proliferation. In summary, our results identify novel mRNA/miRNA interactions that contribute to pediatric glioma malignancy and represent potential targets for the development of new therapeutic strategies.