The role of tristetraprolin in control of breast cancer progression

描述(申请人提供)：肿瘤细胞表达促肿瘤因子，如细胞因子和脂类分子，在肿瘤生长和转移中起关键作用。然而，肿瘤细胞产生这些因子的机制在很大程度上仍不清楚。最近，我们发现一种锌指蛋白TTP(tristetraprolin，TTP)在乳腺肿瘤和肿瘤细胞中的表达显著降低。更重要的是，在小鼠乳腺肿瘤模型中，TTP缺乏的小鼠表现出转移增加和存活率降低。因此，我们假设乳腺肿瘤细胞中TTP的表达受损可能通过增强肿瘤促进因子的表达来促进肿瘤的转移。TTP可能成为乳腺癌治疗的新靶点。TTP是CCCH串联锌指蛋白的一员，参与转录后水平的炎症反应调节。TTP与3‘非翻译区富含腺嘌呤尿苷的元件(Ares)结合，导致编码肿瘤坏死因子-1、粒-巨噬细胞集落刺激因子等的mRNAs失稳。在TTP基因敲除的小鼠中，致炎细胞因子的过度产生会导致严重的全身炎症反应，包括关节炎、自身免疫和髓系增生。总而言之，所有证据表明，TTP是一种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，TTP在乳腺肿瘤中的表达降低与肿瘤微环境中Th17细胞的增加和IL-23的表达增强有关。已有研究表明，IL-23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，TTP在乳腺癌细胞中的过表达抑制了IL-23的表达。鉴于乳腺肿瘤细胞IL-23表达增强和TTP表达下调的分子机制尚不清楚，本研究拟从以下几个方面探讨TTP抑制乳腺肿瘤细胞IL-23表达的分子机制和信号转导途径；(2)明确调控乳腺肿瘤细胞TTP表达的分子机制；(3)评价靶向肿瘤细胞IL-23和TTP表达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，并最终开发能够以肿瘤特异性方式重建TTP在乳腺肿瘤中表达的治疗方法，作为一种新的乳腺癌治疗方法。

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.