title: Identification of IGF-1-enhanced cytokine expressions targeted by miR-181d in glioblastomas via an integrative miRNA/mRNA regulatory network analysis.
abstract: The insulin-like growth factor (IGF)-1 signaling is relevant in regulating cell growth and cytokine secretions by glioblastomas. MicroRNAs determine the cell fate in glioblastomas. However, relationships between IGF-1 signaling and miRNAs in glioblastoma pathogenesis are still unclear. Our aim was to validate the IGF-1-mediated mRNA/miRNA regulatory network in glioblastomas. Using in silico analyses of mRNA array and RNA sequencing data from The Cancer Genome Atlas (TCGA), we identified 32 core enrichment genes that were highly associated with IGF-1-promoted cytokine-cytokine receptor interactions. To investigate the IGF-1-downregulated miRNA signature, microarray-based approaches with IGF-1-treated U87-MG cells and array data in TCGA were used. Four miRNAs, including microRNA (miR)-9-5p, miR-9-3p, miR-181d, and miR-130b, exhibited an inverse correlation with IGF-1 levels. The miR-181d, that targeted the most IGF-1-related cytokine genes, was significantly reduced in IGF-1-treated glioma cells. Statistical models incorporating both high-IGF-1 and low-miR-181d statuses better predicted poor patient survival, and can be used as an independent prognostic factor in glioblastomas. The C-C chemokine receptor type 1 (CCR1) and interleukin (IL)-1b demonstrated inverse correlations with miR-181d levels and associations with patient survival. miR-181d significantly attenuated IGF-1-upregulated CCR1 and IL-1b gene expressions. These findings demonstrate a distinct role for IGF-1 signaling in glioma progression via miR-181d/cytokine networks.
authors.affiliation: Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan.
authors.forename: Kuo-Hao
authors.initials: KH
authors.lastname: Ho
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Peng-Hsu
authors.initials: PH
authors.lastname: Chen
authors.affiliation: Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
authors.forename: Edward
authors.identifier: http://orcid.org/0000-0002-8272-6707
authors.initials: E
authors.lastname: Hsi
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chwen-Ming
authors.initials: CM
authors.lastname: Shih
authors.affiliation: Department of Clinical Pharmacy, Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan.|Department of Pharmacy, Taipei Medical University-Wanfang Hospital, Taipei, Taiwan.
authors.forename: Wei-Chiao
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chia-Hsiung
authors.identifier: http://orcid.org/0000-0003-0307-9650
authors.initials: CH
authors.lastname: Cheng
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Cheng-Wei
authors.initials: CW
authors.lastname: Lin
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan. kuchung@tmu.edu.tw.|Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. kuchung@tmu.edu.tw.
authors.forename: Ku-Chung
authors.identifier: http://orcid.org/0000-0002-4696-3924
authors.initials: KC
authors.lastname: Chen
mesh_terms: D020413:3' Untranslated Regions; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods; D016207:Cytokines / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D011379:Prognosis; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics*; D059467:Transcriptome
chemical_list: D020413:3' Untranslated Regions; D016207:Cytokines; C583557:IGF1 protein, human; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I