title: The NF-κB RelB protein is an oncogenic driver of mesenchymal glioma.
abstract: High-grade gliomas, such as glioblastomas (GBMs), are very aggressive, invasive brain tumors with low patient survival rates. The recent identification of distinct glioma tumor subtypes offers the potential for understanding disease pathogenesis, responses to treatment and identification of molecular targets for personalized cancer therapies. However, the key alterations that drive tumorigenesis within each subtype are still poorly understood. Although aberrant NF-κB activity has been implicated in glioma, the roles of specific members of this protein family in tumorigenesis and pathogenesis have not been elucidated. In this study, we show that the NF-κB protein RelB is expressed in a particularly aggressive mesenchymal subtype of glioma, and loss of RelB significantly attenuated glioma cell survival, motility and invasion. We find that RelB promotes the expression of mesenchymal genes including YKL-40, a marker of the MES glioma subtype. Additionally, RelB regulates expression of Olig2, a regulator of cancer stem cell proliferation and a candidate marker for the cell of origin in glioma. Furthermore, loss of RelB in glioma cells significantly diminished tumor growth in orthotopic mouse xenografts. The relevance of our studies for human disease was confirmed by analysis of a human GBM genome database, which revealed that high RelB expression strongly correlates with rapid tumor progression and poor patient survival rates. Thus, our findings demonstrate that RelB is an oncogenic driver of mesenchymal glioma tumor growth and invasion, highlighting the therapeutic potential of inhibiting the noncanonical NF-κB (RelB-mediated) pathway to treat these deadly tumors.
authors: Department of Molecular & Cellular Medicine, Texas A&M University Health Science Center, College Station, Texas, United States of America.
authors: Dong Whan
authors: DW
authors: Lee
authors: Dhivya
authors: D
authors: Ramakrishnan
authors: John
authors: J
authors: Valenta
authors: Ian F
authors: IF
authors: Parney
authors: Kayla J
authors: KJ
authors: Bayless
authors: Raquel
authors: R
authors: Sitcheran
mesh_terms: D054392:Adipokines / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D000071451:Chitinase-3-Like Protein 1; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D037102:Lectins / Q000235:genetics / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D051841:Transcription Factor RelB / Q000235:genetics* / Q000378:metabolism
chemical_list: D054392:Adipokines; D051792:Basic Helix-Loop-Helix Proteins; D000071451:Chitinase-3-Like Protein 1; D037102:Lectins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D051841:Transcription Factor RelB; C084533:CHI3L1 protein, human; C405708:OLIG2 protein, human; C497593:RELB protein, human