title: Targeting of TGFβ signature and its essential component CTGF by miR-18 correlates with improved survival in glioblastoma.
abstract: The miR-17∼92 cluster is thought to be an oncogene, yet its expression is low in glioblastoma multiforme (GBM) cell lines. This could allow unfettered expression of miR-17∼92 target genes such as connective tissue growth factor (CTGF; or CCN2), which is known to contribute to GBM pathogenesis. Indeed, microRNA-18a (but not other miR-17∼92 members) has a functional site in the CTGF 3' UTR, and its forced reexpression sharply reduces CTGF protein and mRNA levels. Interestingly, it also reduces the levels of CTGF primary transcript. The unexpected effects of miR-18a on CTGF transcription are mediated in part by direct targeting of Smad3 and ensuing weakening of TGFβ signaling. Having defined the TGFβ signature in GBM cells, we demonstrate a significant anti-correlation between miR-18 and TGFβ signaling in primary GBM samples from The Cancer Genome Atlas. Most importantly, high levels of miR-18 combined with low levels of the TGFβ metagene correlate with prolonged patient survival. Thus, low expression of the miR-17∼92 cluster, and specifically miR-18a, could significantly contribute to GBM pathogenesis.
authors.affiliation: Division of Cancer Pathobiology, Department of Pathology & Laboratory Medicine, Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Fox
authors.forename: Michael
authors.initials: M
authors.lastname: Dews
authors.forename: Andy J
authors.initials: AJ
authors.lastname: Minn
authors.forename: Andrei
authors.initials: A
authors.lastname: Thomas-Tikhonenko
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D045744:Cell Line, Tumor; D055513:Connective Tissue Growth Factor / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D052138:Genes, Neoplasm / Q000235:genetics; D005909:Glioblastoma / Q000401:mortality / Q000473:pathology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; C526317:CCN2 protein, human; C524941:MIRN17 microRNA, human; C522576:MIRN18A microRNA, human; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor