Interferon-induced tumor-suppressive activity of Absent in Melanoma 2 (AIM2) in gastrointestinal cancers

黑色素瘤缺失 2 (AIM2) 在胃肠道癌症中的干扰素诱导肿瘤抑制活性

• 批准号: 92054903
• 负责人: Professorin Dr. Susanne Dihlmann
• 金额: --
• 依托单位: Klinik für Gefäßchirurgie und Endovaskuläre Chirurgie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2008
• 资助国家: 德国
• 起止时间: 2007-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/92054903?language=en
• 关键词: Interferon; induced; tumor; suppressive; activity

During carcinogenesis tumor cells are continuously exposed to different types of immune cells. Some of these cells release interferons (IFNs), a family of cytokines that mediate pro-and antiinflammatory as well as tumor-suppressive functions. Although the receptors and intracellular signaling components of the IFN-signaling pathway are well understood, little is known about the function of IFN-induced target genes and their role in tumor suppression. We recently examined in detail alterations of the absent in melanoma 2 (AIM2) gene that belongs to the HIN-200 family of IFNinducible proteins. AIM2 shows a high frequency of frameshift mutations in microsatellite unstable (MSI-H) colorectal, gastric, and endometrial tumors. In addition, it is affected by other mutations and promoter silencing in primary colon cancers and cell lines, suggesting that its inactivation might be involved in tumor escape mechanisms. Supporting evidence came from stable restoration of recombinant AIM2 in AIM2-deficient cells which clearly suppressed colony formation, cell proliferation and viability by reducing endogenous and TNF-α stimulated nuclear factor kappa B (NF-kB) signaling activity. Interestingly, there was no evidence for the (A9) frameshift mutation to affect any of the analyzed AIM2 functions. Microarray-based differential expression analysis revealed substantial AIM2- induced up-regulation of genes involved in immunomodulation, such as IFN-responsive, -inducing or - enhancing genes, and genes involved in cell-cell signaling. Moreover, a great number of genes that was down-regulated upon constitutive AIM2 expression point to a role of AIM2 in regulation of cancer related lipid metabolism. The studies applied for here aim to understand the tumor suppressive mechanism of AIM2 in more detail. Accordingly, both, downstream effects and upstream mechanisms of AIM2 expression will be analyzed. In particular, we will characterize AIM2-responsive target genes to link IFN-mediated anti-tumor effects, cell differentiation and cancer related metabolism. In addition, AIM2-responsiveness to other cytokines and JAK/STAT-mediated activation of AIM2 expression will be studied to link cytokine signaling to induction of AIM2. Our studies shall add to understanding cytokine (IFN and others) -mediated anti-tumor effects and putative tumor escape mechanisms thereby providing the basis for development of novel anti-cancer therapies.

在癌变过程中，肿瘤细胞不断暴露于不同类型的免疫细胞。其中一些细胞会释放干扰素 (IFN)，这是一种介导促炎、抗炎以及肿瘤抑制功能的细胞因子家族。尽管 IFN 信号通路的受体和细胞内信号成分已被充分了解，但人们对 IFN 诱导的靶基因的功能及其在肿瘤抑制中的作用知之甚少。我们最近详细检查了黑色素瘤缺失 2 (AIM2) 基因的变化，该基因属于 IFN 诱导蛋白的 HIN-200 家族。 AIM2 在微卫星不稳定 (MSI-H) 结直肠癌、胃肿瘤和子宫内膜肿瘤中显示出高频率的移码突变。此外，它还受到原发性结肠癌和细胞系中其他突变和启动子沉默的影响，表明它的失活可能与肿瘤逃逸机制有关。支持证据来自 AIM2 缺陷细胞中重组 AIM2 的稳定恢复，通过减少内源性和 TNF-α 刺激的核因子 kappa B (NF-kB) 信号活性，明显抑制集落形成、细胞增殖和活力。有趣的是，没有证据表明 (A9) 移码突变会影响任何分析的 AIM2 功能。基于微阵列的差异表达分析揭示了AIM2诱导的免疫调节相关基因的显着上调，例如IFN反应性、诱导性或增强性基因，以及细胞间信号传导相关的基因。此外，大量 AIM2 组成型表达下调的基因表明 AIM2 在调节癌症相关脂质代谢中发挥作用。本次申请的研究旨在更详细地了解AIM2的肿瘤抑制机制。因此，将分析 AIM2 表达的下游效应和上游机制。特别是，我们将表征 AIM2 响应靶基因，以将 IFN 介导的抗肿瘤作用、细胞分化和癌症相关代谢联系起来。此外，还将研究 AIM2 对其他细胞因子的反应性以及 JAK/STAT 介导的 AIM2 表达激活，以将细胞因子信号转导与 AIM2 的诱导联系起来。我们的研究将有助于了解细胞因子（干扰素和其他）介导的抗肿瘤作用和假定的肿瘤逃逸机制，从而为新型抗癌疗法的开发提供基础。