The role of tristetraprolin in control of breast cancer progression

描述（申请人提供）：肿瘤细胞中细胞因子、脂质分子等促肿瘤因子的表达在肿瘤生长和转移过程中起着至关重要的作用。然而，肿瘤细胞产生这些因子的机制在很大程度上仍然未知。最近，我们发现tristetrprolin （TTP）是一种促进许多靶基因mRNA衰变的锌指蛋白，在乳腺肿瘤和肿瘤细胞中的表达明显降低。更重要的是，在小鼠乳腺肿瘤模型中，TTP缺陷小鼠表现出转移增加和生存降低。因此，我们假设TTP在乳腺肿瘤细胞中的表达受损是通过增强促瘤因子的表达来促进肿瘤转移的。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，在转录后水平参与炎症反应的调节。TTP与3‘非翻译区（3’ utr）内的富腺嘌呤-尿苷元素（AREs）结合，导致编码TNF-1、GM-CSF等mrna的不稳定。在TTP敲除小鼠中，促炎细胞因子的过量产生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，所有证据表明TTP是参与控制炎症和维持体内平衡的关键蛋白。我们最近发现乳腺肿瘤中TTP表达的降低与肿瘤微环境中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，TTP在乳腺肿瘤细胞中的过表达可抑制IL-23的表达。由于乳腺肿瘤细胞中IL-23表达增强和TTP表达降低的分子机制尚不清楚，本研究拟：(1)探讨TTP抑制乳腺肿瘤细胞中IL-23表达的分子机制和信号通路；(2)明确乳腺肿瘤细胞中TTP表达调控的分子机制；(3)评价靶向肿瘤细胞中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、分子和免疫机制，并最终开发出能够以肿瘤特异性方式重建TTP在乳腺肿瘤中的表达的治疗方法，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.