title: Id4 suppresses MMP2-mediated invasion of glioblastoma-derived cells by direct inactivation of Twist1 function.
abstract: Tumor cell invasion is a major contributor to cancer morbidity, and is of particular importance in patients with glioblastoma multiforme (GBM), the highest grade and most aggressive primary brain tumor. Tumor cell invasion and the expression of matrix metalloproteinases (MMPs), which are required for GBM invasion, are enhanced by inhibitor of DNA binding (Id) gene family members, Id1, Id2 and Id3, which can be highly expressed in glioma. Id4 is expressed in GBM at more variable levels than these other family members and we sought to determine its role in invasion. We found, unexpectedly, that invasion was dramatically inhibited in cells expressing Id4 as a result of decreased MMP2, a secreted proteinase key for brain tumor invasion. We demonstrate that Id4 decreased MMP2 expression by a direct inhibitory interaction with Twist1, a basic helix-loop-helix transcription factor known to increase MMP2 expression. Importantly, using data from The Cancer Genome Atlas, we show that Id4 expression correlates with survival of glioblastoma patients and inversely correlates with MMP2 expression. These data suggest that the upregulation of MMP2 resulting from decreased Id4 expression in GBM may contribute to the morbidity and mortality of GBM patients.
authors.affiliation: 1] Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH, USA [2] Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Rahme
authors.affiliation: 1] Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH, USA [2] Department of Pediatrics, Geisel School of Medicine at Dartmouth, Hanover, NH, USA [3] Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Israel
mesh_terms: D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D005909:Glioblastoma / Q000378:metabolism*; D005910:Glioma / Q000473:pathology; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000378:metabolism*; D011379:Prognosis; D011485:Protein Binding; D016896:Treatment Outcome; D051879:Twist-Related Protein 1 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C490128:ID4 protein, human; D051796:Inhibitor of Differentiation Proteins; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2