循环肿瘤细胞Stat3/Twist双信号通路交互作用对EMT编程的乳腺癌转移的调控与干预

项目名称： 循环肿瘤细胞Stat3/Twist双信号通路交互作用对EMT编程的乳腺癌转移的调控与干预

项目编号： No.81472489

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王丽华

作者单位： 潍坊医学院

项目金额： 72万元

中文摘要： 文献和我们的临床观察均表明乳腺癌转移与循环肿瘤细胞(CTCs)变化密切相关。上皮-间充质表型转换(EMT)及逆转换MET在体内可塑性编程赋予CTCs侵袭性和肿瘤干细胞性，EMT 转录因子如Twist和Stat3 信号通路均可调节EMT。但Stat3与EMT转录因子交互作用对乳腺癌循环肿瘤细胞影响迄今尚无报道。在前期研究中我们发现Stat3与核受体交互作用影响其靶基因转录和癌细胞生长。我们推测Stat3/Twist的交互作用可能亦参与EMT编程调控的癌转移。因此本项目将应用小鼠乳癌原位和转移模型、人CTC移植裸鼠临床前模型，通过动态观察CTCs其EMT/MET转换和CSC表型，研究Stat3/Twist交互作用对CTC形成、生存、凋亡，逃逸和定植的影响；寻找受Stat3/Twist调控的转移相关基因；探讨不同Stat3抑制剂靶向干预癌转移的可行性。这对于癌转移机制阐明与治疗具有重要意义。

中文关键词： 循环肿瘤细胞；Stat3；交互作用；上皮-间充质表型转换；转移性乳腺癌

英文摘要： Metastasis is responsible for the majority of breast cancer-related deaths. The presence of CTCs is a robust independent prognostic indicator of progression-free survival and overall survival in patients with metastatic breast cancer. Our recent preliminary clinical data also shows that CTCs changes in breast cancer patients are associated with metastasis. Emerging evidence indicates that the epithelial-to-mesenchymal transition (EMT) and breast cancer stem cells (CSCs) cooperate to produce circulating tumor cells (CTCs) that are highly competent for metastasis; whereas, the reverse process-MET is thought to allow the outgrowth of these cells at distant sites.Both EMT transcriptional factors (EMT-TFs) and Stat3 signal pathway have been shown to affect EMT process. However, it is unclear whether the crosstalk between Stat3 and EMT-TFs affects CTCs in vivo during the process of metastasis. In previous studies, we have reported that the role of Stat3 interaction with nuclear receptors in gene transcription and tumor cell growth. We hypothesize that Stat3 may interacts with Twist1, a major EMT transcription factor, in CTCs, which may regulate the plasticity in EMT in metastasis of breast cancer.We proposed the present study with three specific aims: 1) to investigate the effects of Stat3/Twist crosstalk in dynamic alterations ofCTC numbers, EMT/MET program and CSCphenotypeand their association with the generation, survival, apoptosis, immunoescape and colonization of CTCs,by using mouse primary breast tumor model, mouse metastatic models including spontaneous and experimental lung metastatic model, and patients CTC xenograftmouse model; 2) to identify Stat3/Twist-targeted genes that are associated with invasion and metastasisby comparing gene expression patterns associated with individual steps of mammary tumor metastasis; and 3) to explore the feasibility of targeted intervention of different types of Stat3 inhibitors on breast cancer metastasis. These studies will significantly promote our understanding of the role of CTCs and provide a novel strategy to the treatment in breast cancer metastasis.

英文关键词： Circulating Tumor Cells;Stat3;Crosstalk;Epithelial-to-mesenchymal transition;Metastatic breast cancer