title: Eva1 Maintains the Stem-like Character of Glioblastoma-Initiating Cells by Activating the Noncanonical NF-κB Signaling Pathway.
abstract: Glioblastoma (GBM)-initiating cells (GIC) are a tumorigenic subpopulation that are resistant to radio- and chemotherapies and are the source of disease recurrence. Therefore, the identification and characterization of GIC-specific factors is critical toward the generation of effective GBM therapeutics. In this study, we investigated the role of epithelial V-like antigen 1 (Eva1, also known as myelin protein zero-like 2) in stemness and GBM tumorigenesis. Eva1 was prominently expressed in GICs in vitro and in stem cell marker (Sox2, CD15, CD49f)-expressing cells derived from human GBM tissues. Eva1 knockdown in GICs reduced their self-renewal and tumor-forming capabilities, whereas Eva1 overexpression enhanced these properties. Eva1 deficiency was also associated with decreased expression of stemness-related genes, indicating a requirement for Eva1 in maintaining GIC pluripotency. We further demonstrate that Eva1 induced GIC proliferation through the activation of the RelB-dependent noncanonical NF-κB pathway by recruiting TRAF2 to the cytoplasmic tail. Taken together, our findings highlight Eva1 as a novel regulator of GIC function and also provide new mechanistic insight into the role of noncanonical NF-κB activation in GIC, thus offering multiple potential therapeutic targets for preclinical investigation in GBM.
authors.affiliation: Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ohtsu
authors.affiliation: Laboratory for Cell Lineage Modulation, RIKEN Center for Developmental Biology, Kobe, Hyogo, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nakatani
authors.affiliation: Department of Neurosurgery, Ehime University Graduate School of Medicine, To-on, Ehime, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamashita
authors.affiliation: Department of Neurosurgery, Ehime University Graduate School of Medicine, To-on, Ehime, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Ohue
authors.affiliation: Department of Neurosurgery, Ehime University Graduate School of Medicine, To-on, Ehime, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Ohnishi
authors.affiliation: Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan. Laboratory for Cell Lineage Modulation, RIKEN Center for Developmental Biology, Kobe, Hyogo, Japan. tkondo@igm.hokudai.ac.jp.
authors.forename: Toru
authors.initials: T
authors.lastname: Kondo
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D015815:Cell Adhesion Molecules; C112474:MPZL2 protein, human; D016328:NF-kappa B