Cytokine induced RelB/p50 complexes drive mesenchymal glioma progression

 描述（由申请人提供） 在过去的25年里，在诊断为多形性胶质母细胞瘤（GBM）后，患者的生存率几乎没有改善。强烈诱导血管生成，对辐射的极端抗性，以及高度侵袭性的侵袭性表型使GBM成为最致命和最难治疗的人类癌症之一。最近，GBM的间充质亚型已被鉴定为显示最具浸润性的行为，对标准疗法最具抗性，并表达与最差患者预后相关的标记物，如分泌蛋白YKL-40。我们已经确定了两种促炎细胞因子，白细胞介素-1 β（IL-1β）和抑瘤素M（OSM），在间质GBM患者中特异性过表达。我们的数据表明，IL-1β和OSM协同作用，通过一种新的RelB/p50经典途径支持GBM进展，迄今为止，该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确定了GBM细胞和星形胶质细胞中的两组RelB/p50依赖性基因：“保守”基因（在GBM和星形胶质细胞中激活）和“异常激活”基因（在GBM中激活，但在星形胶质细胞中抑制）。“保守”基因包括间充质GBM亚型的标记物和假定调节GBM进展的有趣的新基因。“异常激活”基因编码许多细胞因子，包括IL-1，这表明存在RelB驱动的前馈细胞因子环，助长GBM中的慢性炎症。重要的是，“异常激活”基因先前已被证明通过巨噬细胞中的表观遗传沉默进行RelB依赖性重编程，这需要组蛋白脱乙酰酶SIRT 1。我们的初步研究发现，sirt 1基因的一个等位基因在75%的GBM肿瘤中缺失，这可以解释GBM中缺乏RelB依赖的表观遗传沉默。因此，我们假设RelB/p50激活驱动诱导慢性炎症和GBM侵袭性的基因表达程序。

 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.