Cytokine induced RelB/p50 complexes drive mesenchymal glioma progression

细胞因子诱导的 RelB/p50 复合物驱动间充质胶质瘤进展

• 批准号: 9050158
• 负责人: Michael Waters
• 金额: $ 3.51万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-25 至 2021-03-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9050158
• 关键词: Aggressive behavior; Alleles; Astrocytes; Behavior; Categories; Cell Death; Cell Line; Cells; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Computational algorithm; Cranial Irradiation; Data; Diagnosis; Dimerization; Environment; Epigenetic Process; Extensive Necrosis; Future; Gene Expression; Genes; Glioblastoma; Glioma; Hematopoietic; Histone Deacetylase; Human; Immunocompetent; In Vitro; Inflammation; Inflammatory; Injection of therapeutic agent; Interleukin-1; Interleukin-1 beta; Malignant Neoplasms; Malignant neoplasm of brain; Mesenchymal; Microarray Analysis; Modeling; Molecular; Monitor; Mus; Mutation; Pathway interactions; Patients; Phenotype; Production; Proteins; Radiation; Radioresistance; Resistance; Role; Signal Transduction; TNFRSF5 gene; Testing; Therapeutic Intervention; angiogenesis; cytokine; dimer; feeding; in vivo; in vivo Model; macrophage; novel; oncostatin M; outcome forecast; overexpression; p65; programs; public health relevance; research study; tumor; tumor growth; tumor progression

 DESCRIPTION (provided by applicant) In the past 25 years, little improvement has been made in patient survival after a diagnosis of glioblastoma multiforme (GBM). The robust induction of angiogenesis, extreme resistance to radiation, and a highly aggressive, invasive phenotype make GBM one of the most lethal and difficult human cancers to treat. Recently, a mesenchymal subtype of GBMs has been identified that displays the most infiltrative behavior, is the most resistant to standard therapies, and expresses markers, such as a secreted protein YKL-40, which correlate with the worst patient prognosis. We have identified that two proinflammatory cytokines, interleukin-1β (IL-1β) and oncostatin M (OSM), are specifically overexpressed in patients with mesenchymal GBM. Our data indicates that IL-1β and OSM synergize to support GBM progression through a novel RelB/p50-canonical pathway, which to date has only been proposed to function in cells expressing high levels of RelB. Our preliminary studies have identified two groups of RelB/p50-dependent genes in GBM cells and astrocytes: "conserved" genes (activated in both GBM and astrocytes) and "aberrantly-activated" genes (activated in GBM but suppressed in astrocytes). The "conserved" genes include markers of the mesenchymal GBM subtype and intriguing novel genes postulated to regulate GBM progression. The "aberrantly activated" genes encode many cytokines, including IL-1, which suggests the existence of RelB-driven feedforward cytokine loop fueling chronic inflammation in GBM. Importantly, the "aberrantly-activated" genes have previously been shown to undergo RelB-dependent reprograming by epigenetic silencing in macrophages, which requires histone deacetylase SIRT1. Our preliminary studies have found that one allele of the sirt1 gene is deleted in 75% of GBM tumors, which may explain the lack of RelB-dependent epigenetic silencing in GBM. Thus, we hypothesize that RelB/p50 activation drives gene expression programs which induced both chronic inflammation and GBM aggressiveness.

 描述(由申请人提供) 在过去的25年里，在被诊断为多形性胶质母细胞瘤(GBM)后，患者的存活率几乎没有改善。强大的血管生成诱导，对辐射的极端抵抗力，以及高度侵袭性和侵袭性的表型使GBM成为最致命和最难治疗的人类癌症之一。最近，已发现一种间充质细胞亚型，它表现出最具浸润性的行为，对标准治疗最具抵抗力，并表达与最差患者预后相关的标志物，如分泌蛋白YKL-40。我们已经发现两种促炎细胞因子，白介素1β(IL-1β)和抑癌素M(Osm)在间叶性基底膜患者中特异性地过度表达。我们的数据表明，IL-1β和OSM通过一种新的RelB/p50-规范途径协同支持基底膜的进展，到目前为止，这一途径仅被认为在表达高水平RelB的细胞中起作用。我们的初步研究已经在GBM细胞和星形胶质细胞中发现了两组依赖RelB/p50的基因：“保守”基因(在GBM和星形胶质细胞中都激活)和“异常激活”基因(在GBM中激活，但在星形胶质细胞中抑制)。这些“保守的”基因包括间充质基底膜亚型的标记，以及被认为调节基底膜进展的有趣的新基因。这些“异常激活”的基因编码许多细胞因子，包括IL-1，这表明存在由RelB驱动的前馈细胞因子环，助长了GBM的慢性炎症。重要的是，“异常激活”的基因此前已被证明在巨噬细胞中通过表观遗传沉默而经历了依赖于RelB的重新编程，这需要组蛋白脱乙酰基酶SIRT1。我们的初步研究发现，在75%的GBM肿瘤中，SIRT1基因的一个等位基因缺失，这可能解释了GBM中缺乏RelB依赖的表观遗传沉默。因此，我们假设RelB/p50激活驱动基因表达程序，从而诱导慢性炎症和GBM侵袭性。