title: miR-218 opposes a critical RTK-HIF pathway in mesenchymal glioblastoma.
abstract: Glioblastoma multiforme (GBM) and the mesenchymal GBM subtype in particular are highly malignant tumors that frequently exhibit regions of severe hypoxia and necrosis. Because these features correlate with poor prognosis, we investigated microRNAs whose expression might regulate hypoxic GBM cell survival and growth. We determined that the expression of microRNA-218 (miR-218) is decreased significantly in highly necrotic mesenchymal GBM, and orthotopic tumor studies revealed that reduced miR-218 levels confer GBM resistance to chemotherapy. Importantly, miR-218 targets multiple components of receptor tyrosine kinase (RTK) signaling pathways, and miR-218 repression increases the abundance and activity of multiple RTK effectors. This elevated RTK signaling also promotes the activation of hypoxia-inducible factor (HIF), most notably HIF2α. We further show that RTK-mediated HIF2α regulation is JNK dependent, via jun proto-oncogene. Collectively, our results identify an miR-218-RTK-HIF2α signaling axis that promotes GBM cell survival and tumor angiogenesis, particularly in necrotic mesenchymal tumors.
authors.affiliation: Abramson Family Cancer Research Institute, Howard Hughes Medical Institute, Penn Molecular Profiling Facility - Bioinformatics Group, and Departments of Cell and Developmental Biology, Pathology and Laboratory Medicine, Cancer Biology, and Radiation Oncology, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Lijoy K
authors.initials: LK
authors.lastname: Mathew
authors.forename: Nicolas
authors.initials: N
authors.lastname: Skuli
authors.forename: Vera
authors.initials: V
authors.lastname: Mucaj
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Lee
authors.forename: Pascal O
authors.initials: PO
authors.lastname: Zinn
authors.forename: Pratheesh
authors.initials: P
authors.lastname: Sathyan
authors.forename: Hongxia Z
authors.initials: HZ
authors.lastname: Imtiyaz
authors.forename: Zhongfa
authors.initials: Z
authors.lastname: Zhang
authors.forename: Ramana V
authors.initials: RV
authors.lastname: Davuluri
authors.forename: Shilpa
authors.initials: S
authors.lastname: Rao
authors.forename: Sriram
authors.initials: S
authors.lastname: Venneti
authors.forename: Priti
authors.initials: P
authors.lastname: Lal
authors.forename: Justin D
authors.initials: JD
authors.lastname: Lathia
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.forename: Brian
authors.initials: B
authors.lastname: Keith
authors.forename: Andy J
authors.initials: AJ
authors.lastname: Minn
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism*; D002470:Cell Survival; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D009336:Necrosis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D020411:Oligonucleotide Array Sequence Analysis; D000090063:Proto-Oncogene Mas; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D055815:Young Adult; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D035683:MicroRNAs; D000090063:Proto-Oncogene Mas; D020794:Receptor Protein-Tyrosine Kinases; D000099162:Endothelial PAS Domain-Containing Protein 1; C000715470:MAS1 protein, human; C547471:MIRN218 microRNA, human; C547684:MIRN218 microRNA, mouse