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.

Ganglioside GD3 Enhances Invasiveness of Gliomas by Forming a Complex with Platelet-derived Growth Factor Receptor α and Yes Kinase

“…resulted in the suppression of tumorigenesis in vivo (45). Intriguingly, it is reported that RAS/PI3K/Akt/IKK/NF-B pathway activated by PDGF was associated with anti-apoptotic signaling (46).…”

RelB/p50 Complexes Regulate Cytokine-Induced YKL-40 Expression

“…In agreement with our current findings indicating that RelB regulates YKL-40 expression, RelB is strongly expressed in mesenchymal subtype of GBM and promotes expression of mesenchymal genes, including YKL-40 (63). Furthermore, loss of RelB expression attenuates GBM cell survival, motility and invasion (64). …”

Hyaluronic Acid Mediated Enrichment of CD44 Expressing Glioblastoma Stem Cells in U251MG Xenograft Mouse Model

“…NFκB complex activates MMP-9 and several other genes which are key response elements in the tumorigenesis and stem cell maintenance through tumor microenvironment mediated inflammation and ECM signaling [30] [31,32]. To test the activation of inflammatory mediators we checked the NFκB activation in the HA-treated spheroids.…”