Cytokine modulated model growth inhibitory mechanisms

细胞因子调节模型生长抑制机制

• 批准号: 7728141
• 负责人: DHAN V. KALVAKOLANU
• 金额: $ 28.1万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-07 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7728141
• 关键词: Affect; Antiviral Agents; Apoptosis; Binding; Biological; Cell Line; Characteristics; Clinical; Clinical Research; Development; Family; Feedback; Functional disorder; Funding; Genes; Genetic; Growth; Growth Inhibitors; Growth Suppressor Genes; Human; Immune response; In Vitro; Interferons; Knock-out; Malignant Neoplasms; Modeling; Molecular; Mutation; Neoplasm Metastasis; Normal Cell; Oncogene Proteins; Oncogenes; Oncogenic; Physiological; Play; Primary Neoplasm; Process; Proteins; Regulatory Pathway; Retinoids; Role; Signal Transduction; Skin Carcinoma; Squamous cell carcinoma; Stat3 protein; System; Time; Transgenic Mice; Tretinoin; Tumor Suppression; Up-Regulation; Vitamin A; Xenograft Model; cell growth; cytokine; immune function; in vivo; in vivo Model; inhibitor/antagonist; mortality; neoplastic cell; new growth; novel; pathogen; public health relevance; response; transcription factor; tumor; tumor growth; viral DNA

DESCRIPTION (provided by applicant): Cytokines regulate neoplastic cell growth in vivo either by inducing the expression of growth suppressor genes in tumors or by mounting an immune response against them. The interferon family of cytokines regulates several physiologic responses such as antiviral, antitumor, and immune functions. By interacting with other cytokines, IFNs become an integral part of a large of intercellular signaling network that promotes anti-tumor and anti-pathogen surveillance system in vivo. In an earlier study, we demonstrated that the IFN-induced anti-tumor actions, especially apoptosis, could be synergistically augmented by all-trans retinoic acid (RA). This vitamin-A metabolite by itself acts as a growth inhibitor in many experimental and clinical models. Some clinical studies also demonstrated the potent tumor inhibitory effects of IFN/RA. We hypothesized that IFN/RA employs novel gene products for suppressing tumor growth. To identify the critical molecules involved in IFN/RA-induced apoptosis, we have used a genetic strategy and identified several Genes associated with Retinoid-Interferon-induced Mortality (GRIM). One such novel gene product, GRIM-19, suppresses growth via apoptosis. Previous studies by us and others showed that its activity suppressed by DNA viral oncoproteins and some cellular proteins. These observations indicate its potent anti-oncogenic characteristics. During the last funding period we have shown that GRIM-19 binds to Signal Transducer and Activator of Transcription 3 (STAT3) and suppresses its growth promoting action using cell line models. STAT3, a dormant cytokine-regulated transcription factor, is constitutively activated in a number of human tumors by oncogenic signals. STAT3 activity is regulated in normal cells by feedback inhibitors. Persistent STAT3 activity promotes survival, proliferation, metastasis of tumor cells by stimulating the expression of various cellular genes involved in those responses. Although oncogenic activation of STAT3 is an important step, we suggest that loss or inactivation of its inhibitors may also play a critical step in this process prior to the promotion of tumor growth. In preliminary studies, we showed that GRIM-19 suppress constitutive STAT3- induced tumor growth and metastasis using xenograft models. Consistent with these, we observed a loss of expression and mutations in GRIM-19 in several primary human tumors, which correlated with a strong upregulation of STAT3-inducible genes and promotion of cell growth. In this renewal application, we will investigate the biological relevance of GRIM-19 to tumor growth in vivo using knockout and transgenic mice. We will investigate the impact of grim19 mutations (found in primary tumors) on oncogene-induced tumor growth promotion using in vitro and in vivo models. Although a deregulation of STAT3 is known in many tumors, the molecular mechanisms of its deregulation, specifically the role of its inhibitors in tumor development are poorly studied. The studies proposed in this application will define how tumor- specific dysfunctions in GRIM-19 affect the functioning of this new growth regulatory pathway. PUBLIC HEALTH RELEVANCE: Cases of Squamous cell carcinoma (SCC), a form of non-melanoma skin cancer (NMSC), are on the rise, with over a million new cases annually in U.S.A. Persistently activated STAT3 is found in many SCCs and other cancers, which correlates with an aggressive growth of tumors. This proposal for the first time will define the importance of GRIM-19, an inhibitor of STAT3, in tumor suppression. The information gained from these studies will be useful in developing designer therapies for treating SCCs and other cancers, where abnormal STAT3 activities are observed.

描述（由申请人提供）：细胞因子通过诱导肿瘤中生长抑制基因的表达或通过对其进行免疫反应来调节体内肿瘤细胞的生长。细胞因子干扰素家族调节几种生理反应，例如抗病毒，抗肿瘤和免疫功能。通过与其他细胞因子相互作用，IFN成为大型细胞间信号网络的组成部分，该网络促进体内促进抗肿瘤和抗病原体监测系统。在较早的研究中，我们证明了IFN诱导的抗肿瘤作用，尤其是凋亡，可以通过全反式视黄酸（RA）协同增强。在许多实验和临床模型中，这种维生素-A代谢产物本身就是一种生长抑制剂。一些临床研究还证明了IFN/RA的有效肿瘤抑制作用。我们假设IFN/RA采用新型基因产物来抑制肿瘤生长。为了鉴定IFN/RA诱导的凋亡涉及的关键分子，我们使用了遗传策略，并鉴定了几种与类维生素性相互作用诱导的死亡率（GRIM）相关的基因。一种这种新型基因产物Grim-19可通过细胞凋亡抑制生长。我们和其他人的先前研究表明，其活性被DNA病毒癌蛋白和某些细胞蛋白抑制。这些观察结果表明其有效的抗疾病特征。在最后一个资金期间，我们表明GRIM-19与转录3（STAT3）的信号转换器和激活因子结合，并使用细胞系模型抑制其生长促进作用。 Stat3是一种休眠的细胞因子调节的转录因子，通过致癌信号在许多人类肿瘤中被组成症。 STAT3活性通过反馈抑制剂在正常细胞中调节。持续的STAT3活性通过刺激参与这些反应的各种细胞基因的表达来促进肿瘤细胞的生存，增殖，转移。尽管STAT3的致癌激活是一个重要的步骤，但我们认为在促进肿瘤生长之前，其抑制剂的损失或失活也可能在此过程中起关键步骤。在初步研究中，我们表明GRIM-19使用异种移植模型抑制构型STAT3诱导肿瘤的生长和转移。与这些一致，我们观察到在几种原发性人类肿瘤中Grim-19中表达和突变的丧失，这与STAT3诱导基因的强上调和细胞生长的促进相关。在此续签应用中，我们将使用敲除和转基因小鼠研究Grim-19与体内肿瘤生长的生物学相关性。我们将研究Grim19突变（在原发性肿瘤中发现）对使用体外和体内模型促进肿瘤诱导的肿瘤生长的影响。尽管在许多肿瘤中已知对STAT3的放松管制，但对其失调的分子机制，特别是其抑制剂在肿瘤发育中的作用的研究很少。该应用中提出的研究将定义GRIM-19中肿瘤功能障碍如何影响这种新的生长调节途径的功能。公共卫生相关性：一种非黑色素瘤皮肤癌（NMSC）的鳞状细胞癌病例（SCC）正在上升，每年在美国每年有超过一百万个新病例。该提案首次将定义肿瘤抑制作用Grim-19的重要性。从这些研究中获得的信息将有助于开发用于治疗SCC和其他癌症（观察到异常STAT3活性）的设计师疗法。