title: miR-219-5p inhibits receptor tyrosine kinase pathway by targeting EGFR in glioblastoma.
abstract: Glioblastoma is one of the common types of primary brain tumors with a median survival of 12-15 months. The receptor tyrosine kinase (RTK) pathway is known to be deregulated in 88% of the patients with glioblastoma. 45% of GBM patients show amplifications and activating mutations in EGFR gene leading to the upregulation of the pathway. In the present study, we demonstrate that a brain specific miRNA, miR-219-5p, repressed EGFR by directly binding to its 3'-UTR. The expression of miR-219-5p was downregulated in glioblastoma and the overexpression of miR-219-5p in glioma cell lines inhibited the proliferation, anchorage independent growth and migration. In addition, miR-219-5p inhibited MAPK and PI3K pathways in glioma cell lines in concordance with its ability to target EGFR. The inhibitory effect of miR-219-5p on MAPK and PI3K pathways and glioma cell migration could be rescued by the overexpression of wild type EGFR and vIII mutant of EGFR (both lacking 3'-UTR and thus being insensitive to miR-219-5p) suggesting that the inhibitory effects of miR-219-5p were indeed because of its ability to target EGFR. We also found significant negative correlation between miR-219-5p levels and total as well as phosphorylated forms of EGFR in glioblastoma patient samples. This indicated that the downregulation of miR-219-5p in glioblastoma patients contribute to the increased activity of the RTK pathway by the upregulation of EGFR. Thus, we have identified and characterized miR-219-5p as the RTK regulating novel tumor suppressor miRNA in glioblastoma.
authors.affiliation: Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Soumya Alige Mahabala
authors.initials: SA
authors.lastname: Rao
authors.forename: Arivazhagan
authors.initials: A
authors.lastname: Arimappamagan
authors.forename: Paritosh
authors.initials: P
authors.lastname: Pandey
authors.forename: Vani
authors.initials: V
authors.lastname: Santosh
authors.forename: Alangar Sathyaranjandas
authors.initials: AS
authors.lastname: Hegde
authors.forename: Bangalore Ashwathnarayanara
authors.initials: BA
authors.lastname: Chandramouli
authors.forename: Kumaravel
authors.initials: K
authors.lastname: Somasundaram
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003114:Colony-Forming Units Assay; D017931:DNA Primers / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism*; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D046228:Microarray Analysis; D016297:Mutagenesis, Site-Directed; D060888:Real-Time Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D020413:3' Untranslated Regions; D017931:DNA Primers; C578248:MIRN219 microRNA, human; D035683:MicroRNAs; C512478:EGFR protein, human; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases