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

基本信息

批准号：
9079413
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
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-08 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9079413
关键词：
3&apos 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 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

项目摘要

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）：促肿瘤因子的表达，例如肿瘤细胞的细胞因子和脂质分子，在肿瘤生长和转移中起关键作用。但是，肿瘤细胞产生这些因素的机制仍然很大程度上未知。最近，我们发现，在乳腺肿瘤和肿瘤细胞中，Tristetraprolin（TTP）的表达显着降低。更重要的是，TTP缺乏小鼠在小鼠乳腺肿瘤模型中显示出增加的转移和降低的存活率。因此，我们假设乳腺肿瘤细胞中TTP表达受损会通过增强肿瘤促进因子的表达来促进肿瘤转移。 TTP可以作为乳腺癌治疗的新型治疗靶标。 TTP是CCCH串联锌指蛋白的成员，并参与了转录后水平的炎症反应的调节。 TTP与3'未翻译区域（3'UTR）内的腺嘌呤 - 尿素元素（ARE）结合，导致编码TNF-1，GM-CSF等人的mRNA不稳定。 TTP敲除小鼠中促炎细胞因子的过量产生导致严重的全身性炎症反应，包括关节炎，自身免疫性和髓样增生。总的来说，所有证据表明TTP是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的降低与Th17细胞的增加相关，并增强了肿瘤微环境中IL-23的表达。 IL-23已显示通过促进肿瘤生长和转移在肿瘤进展中起重要作用。我们的数据首次表明乳腺肿瘤细胞可以像巨噬细胞一样行为，而DC则分泌IL-23。另外，乳腺肿瘤细胞中TTP的表达过度抑制了IL-23表达。由于乳腺肿瘤细胞中增强的IL-23和TTP表达降低的分子机制在很大程度上尚不清楚，因此我们建议：（1）研究TTP在乳腺肿瘤细胞中抑制IL-23表达的分子机制和信号传导途径；（2）确定调节乳腺肿瘤细胞中TTP表达的分子机制；（3）评估靶向IL-23和TTP表达在肿瘤细胞中对乳腺肿瘤生长和转移的治疗作用。我们的长期目标是阐明TTP抑制乳腺肿瘤进展的细胞，分子和免疫学机制，并最终开发出可以以肿瘤特异性方式在乳腺肿瘤中重新构建TTP表达的治疗方法，作为一种新型的乳腺癌治疗。