Eva1 Maintains the Stem-like Character of Glioblastoma-Initiating Cells by Activating the Noncanonical NF-κB Signaling Pathway

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 therapeuti...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2016-01, Vol.76 (1), p.171-181
Main Authors: Ohtsu, Naoki, Nakatani, Yuka, Yamashita, Daisuke, Ohue, Shiro, Ohnishi, Takanori, Kondo, Toru
Format: Article
Language:English
Subjects:
Animals
Brain Neoplasms - genetics
Brain Neoplasms - metabolism
Brain Neoplasms - pathology
Cell Adhesion Molecules - genetics
Cell Adhesion Molecules - metabolism
Female
Glioblastoma - genetics
Glioblastoma - metabolism
Glioblastoma - pathology
Heterografts
Humans
Mice
Mice, Inbred NOD
Mice, SCID
NF-kappa B - metabolism
Signal Transduction
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-15-0884