title: HMGB1 as an autocrine stimulus in human T98G glioblastoma cells: role in cell growth and migration.
abstract: HMGB1 (high mobility group box 1 protein) is a nuclear protein that can also act as an extracellular trigger of inflammation, proliferation and migration, mainly through RAGE (the receptor for advanced glycation end products); HMGB1-RAGE interactions have been found to be important in a number of cancers. We investigated whether HMGB1 is an autocrine factor in human glioma cells. Western blots showed HMGB1 and RAGE expression in human malignant glioma cell lines. HMGB1 induced a dose-dependent increase in cell proliferation, which was found to be RAGE-mediated and involved the MAPK/ERK pathway. Moreover, in a wounding model, it induced a significant increase in cell migration, and RAGE-dependent activation of Rac1 was crucial in giving the tumour cells a motile phenotype. The fact that blocking DNA replication with anti-mitotic agents did not reduce the distance migrated suggests the independence of the proliferative and migratory effects. We also found that glioma cells contain HMGB1 predominantly in the nucleus, and cannot secrete it constitutively or upon stimulation; however, necrotic glioma cells can release HMGB1 after it has translocated from the nucleus to cytosol. These findings provide the first evidence supporting the existence of HMGB1/RAGE signalling pathways in human glioblastoma cells, and suggest that HMGB1 may play an important role in the relationship between necrosis and malignancy in glioma tumours by acting as an autocrine factor that is capable of promoting the growth and migration of tumour cells.
authors.affiliation: Department of Medical Chemistry, Biochemistry and Biotechnology, University of Milan, Segrate, Milan, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Bassi
authors.forename: Paola
authors.initials: P
authors.lastname: Giussani
authors.forename: Viviana
authors.initials: V
authors.lastname: Anelli
authors.forename: Thomas
authors.initials: T
authors.lastname: Colleoni
authors.forename: Marco
authors.initials: M
authors.lastname: Pedrazzi
authors.forename: Mauro
authors.initials: M
authors.lastname: Patrone
authors.forename: Paola
authors.initials: P
authors.lastname: Viani
authors.forename: Bianca
authors.initials: B
authors.lastname: Sparatore
authors.forename: Edon
authors.initials: E
authors.lastname: Melloni
authors.forename: Laura
authors.initials: L
authors.lastname: Riboni
mesh_terms: D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D005909:Glioblastoma / Q000378:metabolism*; D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D009336:Necrosis / Q000503:physiopathology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000096:biosynthesis; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D020928:Mitogen-Activated Protein Kinases