The role of tristetraprolin in control of breast cancer progression

三四脯氨酸在控制乳腺癌进展中的作用

• 批准号: 8860146
• 负责人: Jianguo Liu
• 金额: $ 31.13万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-08 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8860146
• 关键词: 3' Untranslated Regions; 4T1; Adenine; Arthritis; Autoimmunity; Binding; Breast Cancer Cell; Breast Cancer Treatment; Cells; CpG Islands; Data; Dendritic Cells; Elements; Gene Targeting; Goals; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Homeostasis; Human; Hyperplasia; Immunologics; Inflammation; Inflammatory Response; Interleukin-24; Interleukins; Knockout Mice; Lipids; Maintenance; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary gland; Mediating; Messenger RNA; Methylation; Modeling; Molecular; Mus; Myelogenous; Neoplasm Metastasis; Patients; Play; Prostaglandin-Endoperoxide Synthase; Proteins; Regulation; Role; Signal Pathway; TIS11 protein; TNF gene; Therapeutic; Therapeutic Effect; Time; Tumor Necrosis Factor-alpha; Uridine; Zinc Fingers; chemokine; cytokine; interleukin-23; mRNA Decay; macrophage; malignant breast neoplasm; member; mouse model; neoplastic cell; new therapeutic target; novel; overexpression; reconstitution; transcription factor; tumor; tumor growth; tumor microenvironment; tumor progression

DESCRIPTION (provided by applicant): Expression of tumor-promoting factors such as cytokines and lipid molecules from tumor cells play critical roles in tumor growth and metastasis. However, the mechanisms by which tumor cells produce these factors are still largely unknown. Recently, we have found that the expression of tristetraprolin (TTP), a zinc finger protein promoting mRNA decay of many target genes, is markedly reduced in breast tumors and tumor cells. More importantly, TTP deficient mice show increased metastases and reduced survival in a mouse mammary gland tumor model. Therefore, we hypothesize that the impaired TTP expression in breast tumor cells promotes tumor metastases via enhancing expression of tumor-promoting factors. TTP may serve as a novel therapeutic target for breast cancer treatment. TTP is a member of CCCH tandem zinc finger proteins and involved in the regulation of inflammatory responses at the post-transcriptional level. TTP binds to adenine-uridine-rich elements (AREs) within the 3' untranslated region (3'UTR) causing destabilization of mRNAs encoding TNF-1, GM-CSF, et al. Overproduction of the proinflammatory cytokines in TTP knockout mice results in a severe systemic inflammatory response including arthritis, autoimmunity and myeloid hyperplasia. Collectively, all evidence indicates that TTP is a critical protein involved in the control of inflammation and maintenance of homeostasis. We recently found that the reduced TTP expression in breast tumors was correlated with increased Th17 cells and enhanced IL-23 expression in the tumor microenvironment. IL-23 has been shown to play an important role in tumor progression by promoting tumor growth and metastasis. Our data indicate for the first time that breast tumor cells could behave like macrophage and DCs to secrete IL-23. In addition, over- expression of TTP in breast tumor cells suppressed IL-23 expression. Since the molecular mechanisms of the enhanced IL-23 and reduced TTP expression in breast tumor cells are largely unknown, in this study, we propose to: (1) Investigate the molecular mechanisms and signaling pathways by which TTP inhibits IL-23 expression in breast tumor cells; (2) Identify the molecular mechanisms that regulate TTP expression in breast tumor cells; (3) Evaluate the therapeutic effects of targeting IL-23 and TTP expression in tumor cells on breast tumor growth and metastasis. Our long-term goal is to elucidate the cellular, molecular and immunologic mechanisms by which TTP suppresses breast tumor progression, and ultimately to develop therapeutic approaches that could reconstitute TTP expression in breast tumors in a tumor-specific manner as a novel breast cancer treatment.

描述（由申请人提供）：肿瘤细胞中细胞因子和脂质分子等肿瘤促进因子的表达在肿瘤生长和转移中发挥着关键作用。然而，肿瘤细胞产生这些因子的机制仍然很大程度上未知。最近，我们发现三四脯氨酸（TTP）这种促进许多靶基因mRNA衰变的锌指蛋白在乳腺肿瘤和肿瘤细胞中的表达显着降低。更重要的是，TTP 缺陷小鼠在小鼠乳腺肿瘤模型中表现出转移增加和存活率降低。因此，我们推测乳腺肿瘤细胞中TTP表达受损通过增强促癌因子的表达来促进肿瘤转移。 TTP可能作为乳腺癌治疗的新靶点。 TTP 是 CCCH 串联锌指蛋白的成员，参与转录后水平炎症反应的调节。 TTP 与 3' 非翻译区 (3'UTR) 内富含腺嘌呤尿苷的元件 (ARE) 结合，导致编码 TNF-1、GM-CSF 等的 mRNA 不稳定。 TTP 敲除小鼠中促炎细胞因子的过量产生会导致严重的全身炎症反应，包括关节炎、自身免疫和骨髓增生。总的来说，所有证据都表明 TTP 是参与控制炎症和维持体内平衡的关键蛋白质。我们最近发现乳腺肿瘤中 TTP 表达的减少与肿瘤微环境中 Th17 细胞的增加和 IL-23 表达的增强相关。 IL-23已被证明通过促进肿瘤生长和转移在肿瘤进展中发挥重要作用。我们的数据首次表明乳腺肿瘤细胞可以像巨噬细胞和 DC 一样分泌 IL-23。此外，乳腺肿瘤细胞中TTP的过度表达抑制了IL-23的表达。由于乳腺肿瘤细胞中IL-23增强和TTP表达减少的分子机制尚不清楚，因此在本研究中，我们建议：（1）研究TTP抑制乳腺肿瘤细胞中IL-23表达的分子机制和信号通路。肿瘤细胞； (2) 明确乳腺肿瘤细胞中调节TTP表达的分子机制； (3)评估靶向肿瘤细胞中IL-23和TTP表达对乳腺肿瘤生长和转移的治疗效果。我们的长期目标是阐明 TTP 抑制乳腺肿瘤进展的细胞、分子和免疫机制，并最终开发出能够以肿瘤特异性方式重建乳腺肿瘤中 TTP 表达的治疗方法，作为一种新型乳腺癌治疗方法。