The Role of ING4 in Modulating the Tumorigenic Contribution of NF-kB in Gliomas

DESCRIPTION (provided by applicant): Malignant gliomas are an aggressive, highly invasive, neurologically destructive and deadly tumors of the brain.神经胶质瘤的扩散浸润性质是患有这种癌症的患者死亡的主要原因之一。最近，炎症反应失调与神经胶质瘤的病理学有关。 The NF-KB family of transcription factors are responsible for mediating immune/inflammatory responses, and constitutive activation of NF-KB has been correlated with gliomagenesis. NF-KB 的激活通常是短暂的，并受到多种机制的调节，包括与其他蛋白质的相互作用。其中一种蛋白质 ING4 最近被证明可以抑制神经胶质瘤细胞中 NF-KB 介导的 IL-8、IL-6 和 COX-2 的表达。这种抑制可能是通过 ING4 和 p65 NF-KB 亚型之间的相互作用发生的。因此，NF-KB通路和ING4蛋白代表了神经胶质瘤治疗的潜在治疗靶点。 We have made the novel observation that ING4 differentially affects NF-KB-mediated gene induction in human glioma cells, inhibiting IL-8 expression, yet enhancing expression of matrix metalloproteinase-9 (MMP-9). These results suggest that the influence of ING4 on NF-KB-mediated genes is complex, i.e., ING4 may have either a positive or negative effect on gene expression that is dependent on promoter context, co- factor composition, chromatin accessibility, and kinetics of gene expression. We believe that studies to investigate the molecular mechanisms of ING4-mediated regulation of NF-KB activity in gliomas are warranted, focusing on ING4 regulation of expression of IL-8, IL-6, MMP-9 and CXCR4, all genes dependent on NF-KB for activation, and involved in glioma growth, invasion and angiogenesis. We will examine the status and integrity of the ING4 gene and the activation status of NF-KB in human glioma tissues, and determine if correlates exist. The effect of ING4 on NF-KB's ability to translocate into the nucleus, bind DNA in vitro and in vivo, and regulate expression of IL-8, IL-6, MMP-9 and CXCR4 will be analyzed in human glioma cells that inducibly express ING4 (Aim 1).在目标 2 中，翻译研究将验证 ING4 对 NF-KB 介导的体内基因表达的影响。 Human glioma cells inducibly expressing ING4 will be transplanted into the brains of scid mice, and the effects of changes in ING4 expression on NF-KB activity, gene expression, glioma growth, invasion and angiogenesis assessed in vivo. This combination of basic science experimentation and translational studies represent the first systematic study of the functional involvement of NF-KB and ING4 in gliomagenesis, and will lead to a greater understanding of the potential for therapeutic intervention of the NF-KB pathway and/or ING4 in malignant gliomas.

DESCRIPTION (provided by applicant): Malignant gliomas are an aggressive, highly invasive, neurologically destructive and deadly tumors of the brain. The diffusively infiltrative nature of gliomas is one of the major causes of mortality in patients afflicted with this cancer. Recently, dysregulation of the inflammatory response has been implicated in the pathobiology of gliomas. The NF-KB family of transcription factors are responsible for mediating immune/inflammatory responses, and constitutive activation of NF-KB has been correlated with gliomagenesis. NF-KB activation is normally transient and regulated by a variety of mechanisms, including interactions with other proteins. One such protein, ING4, has recently been shown to inhibit NF-KB-mediated expression of IL-8, IL-6 and COX-2 in glioma cells. This inhibition may occur through interactions between ING4 and the p65 NF-KB isoform. Thus, the NF-KB pathway and ING4 protein represent potential therapeutic targets for the treatment of gliomas. We have made the novel observation that ING4 differentially affects NF-KB-mediated gene induction in human glioma cells, inhibiting IL-8 expression, yet enhancing expression of matrix metalloproteinase-9 (MMP-9). These results suggest that the influence of ING4 on NF-KB-mediated genes is complex, i.e., ING4 may have either a positive or negative effect on gene expression that is dependent on promoter context, co- factor composition, chromatin accessibility, and kinetics of gene expression. We believe that studies to investigate the molecular mechanisms of ING4-mediated regulation of NF-KB activity in gliomas are warranted, focusing on ING4 regulation of expression of IL-8, IL-6, MMP-9 and CXCR4, all genes dependent on NF-KB for activation, and involved in glioma growth, invasion and angiogenesis. We will examine the status and integrity of the ING4 gene and the activation status of NF-KB in human glioma tissues, and determine if correlates exist. The effect of ING4 on NF-KB's ability to translocate into the nucleus, bind DNA in vitro and in vivo, and regulate expression of IL-8, IL-6, MMP-9 and CXCR4 will be analyzed in human glioma cells that inducibly express ING4 (Aim 1). In Aim 2, translational studies will validate the influence of ING4 on NF-KB-mediated gene expression in vivo. Human glioma cells inducibly expressing ING4 will be transplanted into the brains of scid mice, and the effects of changes in ING4 expression on NF-KB activity, gene expression, glioma growth, invasion and angiogenesis assessed in vivo. This combination of basic science experimentation and translational studies represent the first systematic study of the functional involvement of NF-KB and ING4 in gliomagenesis, and will lead to a greater understanding of the potential for therapeutic intervention of the NF-KB pathway and/or ING4 in malignant gliomas.