title: Guanylate binding protein 1 is a novel effector of EGFR-driven invasion in glioblastoma.
abstract: Although GBP1 (guanylate binding protein 1) was among the first interferon-inducible proteins identified, its function is still largely unknown. Epidermal growth factor receptor (EGFR) activation by amplification or mutation is one of the most frequent genetic lesions in a variety of human tumors. These include glioblastoma multiforme (GBM), which is characterized by independent but interrelated features of extensive invasion into normal brain parenchyma, rapid growth, necrosis, and angiogenesis. In this study, we show that EGFR activation promoted GBP1 expression in GBM cell lines through a signaling pathway involving Src and p38 mitogen-activated protein kinase. Moreover, we identified YY1 (Yin Yang 1) as the downstream transcriptional regulator regulating EGFR-driven GBP1 expression. GBP1 was required for EGFR-mediated MMP1 (matrix metalloproteinase 1) expression and glioma cell invasion in vitro. Although deregulation of GBP1 expression did not affect glioma cell proliferation, overexpression of GBP1 enhanced glioma cell invasion through MMP1 induction, which required its C-terminal helical domain and was independent of its GTPase activity. Reducing GBP1 levels by RNA interference in invasive GBM cells also markedly inhibited their ability to infiltrate the brain parenchyma of mice. GBP1 expression was high and positively correlated with EGFR expression in human GBM tumors and cell lines, particularly those of the neural subtype. Together, these findings establish GBP1 as a previously unknown link between EGFR activity and MMP1 expression and nominate it as a novel potential therapeutic target for inhibiting GBM invasion.
authors.affiliation: Ludwig Institute for Cancer Research, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Akitake
authors.initials: A
authors.lastname: Mukasa
authors.forename: Maria del-Mar
authors.initials: MM
authors.lastname: Inda
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.forename: Webster
authors.initials: W
authors.lastname: Cavenee
authors.forename: Frank
authors.initials: F
authors.lastname: Furnari
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D017434:Protein Structure, Tertiary; D014183:Transplantation, Heterologous
chemical_list: C490287:GBP1 protein, human; D009363:Neoplasm Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1; D019204:GTP-Binding Proteins