title: Epigenetic regulation of the miR142-3p/interleukin-6 circuit in glioblastoma.
abstract: Epigenetic regulation plays a critical role in glioblastoma (GBM) tumorigenesis. However, how microRNAs (miRNAs) and cytokines cooperate to regulate GBM tumor progression is still unclear. Here, we show that interleukin-6 (IL-6) inhibits miR142-3p expression and promotes GBM propagation by inducing DNA methyltransferase 1-mediated hypermethylation of the miR142-3p promoter. Interestingly, miR142-3p also suppresses IL-6 secretion by targeting the 3' UTR of IL-6. In addition, miR142-3p also targets the 3' UTR and suppresses the expression of high-mobility group AT-hook 2 (HMGA2), leading to inhibition of Sox2-related stemness. We further show that HMGA2 enhances Sox2 expression by directly binding to the Sox2 promoter. Clinically, GBM patients whose tumors present upregulated IL-6, HMGA2, and Sox2 protein expressions and hypermethylated miR142-3p promoter also demonstrate poor survival outcome. Orthotopic delivery of miR142-3p blocks IL-6/HMGA2/Sox2 expression and suppresses stem-like properties in GBM-xenotransplanted mice. Collectively, we discovered an IL-6/miR142-3p feedback-loop-dependent regulation of GBM malignancy that could be a potential therapeutic target.
authors: Institute of Oral Biology, National Yang-Ming University, Taipei 112, Taiwan; Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 112, Taiwan.
authors: Guang-Yuh
authors: GY
authors: Chiou
authors: Institute of Oral Biology, National Yang-Ming University, Taipei 112, Taiwan.
authors: Chian-Shiu
authors: CS
authors: Chien
authors: Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan; Cancer Research Center, National Yang-Ming University, Taipei 112, Taiwan.
authors: Mong-Lien
authors: ML
authors: Wang
authors: School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; Department of Neurosurgery, Taipei Veterans General Hospital, Taipei 112, Taiwan.
authors: Ming-Teh
authors: MT
authors: Chen
authors: Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan; Cancer Research Center, National Yang-Ming University, Taipei 112, Taiwan.
authors: Yi-Ping
authors: YP
authors: Yang
authors: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 413, Taiwan.
authors: Yung-Luen
authors: YL
authors: Yu
authors: Institute of Pharmacology, National Yang-Ming University, Taipei 112, Taiwan; Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 112, Taiwan.
authors: Yueh
authors: Y
authors: Chien
authors: Institute of Pharmacology, National Yang-Ming University, Taipei 112, Taiwan; Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 112, Taiwan.
authors: Yun-Ching
authors: YC
authors: Chang
authors: School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; Department of Neurosurgery, Taichung Veterans General Hospital, Taichung 407, Taiwan.
authors: Chiung-Chyi
authors: CC
authors: Shen
authors: Department of Neurosurgery, Chi-Mei Medical Center, Tainan 710, Taiwan.
authors: Chung-Ching
authors: CC
authors: Chio
authors: Department of Medical Research and Education, Cheng-Hsin General Hospital, Taipei 112, Taiwan.
authors: Kai-Hsi
authors: KH
authors: Lu
authors: Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei 114, Taiwan.
authors: Hsin-I
authors: HI
authors: Ma
authors: Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan; Department of Neurosurgery, Taipei Veterans General Hospital, Taipei 112, Taiwan.
authors: Kuan-Hsuan
authors: KH
authors: Chen
authors: Department of Materials Science and Engineering, National Chiao Tung University, Hsinchu 300, Taiwan.
authors: Dean-Mo
authors: DM
authors: Liu
authors: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Stephanie A
authors: SA
authors: Miller
authors: Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan; School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 112, Taiwan.
authors: Yi-Wei
authors: YW
authors: Chen
authors: Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan; School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 112, Taiwan.
authors: Pin-I
authors: PI
authors: Huang
authors: School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; Department of Neurosurgery, Taipei Veterans General Hospital, Taipei 112, Taiwan.
authors: Yang-Hsin
authors: YH
authors: Shih
authors: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 413, Taiwan; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. Electronic address: mhung@mdanderson.org.
authors: Mien-Chie
authors: MC
authors: Hung
authors: Institute of Pharmacology, National Yang-Ming University, Taipei 112, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan; School of Medicine, National Yang-Ming University, Taipei 112, Taiwan; Cancer Research Center, National Yang-Ming University, Taipei 112, Taiwan; Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 112, Taiwan. Electronic address: shchiou@vghtpe.gov.tw.
authors: Shih-Hwa
authors: SH
authors: Chiou
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005909:Glioblastoma / Q000235:genetics*; D025743:HMGA2 Protein / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D055748:SOXB1 Transcription Factors / Q000235:genetics; D015854:Up-Regulation
chemical_list: D020413:3' Untranslated Regions; D025743:HMGA2 Protein; D015850:Interleukin-6; C555159:MIRN142 microRNA, human; D035683:MicroRNAs; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors