AQP3介导的EMT过程在乳腺癌转移中的作用及其具体机制

Accumulating evidence suggests that aquaporin 3 (AQP3) may facilitate breast cancer metastasis. Supporting this notion, we previously found that the upregulation of AQP3 could enhance migration and invasion of breast cancer cells with triggering cell epithelial-mesenehymal transition (EMT). Despite recent progress, the pathological functions of AQP3 and the molecular pathways connecting AQP3 and EMT in breast cancer are still unclear and need to be better defined. In this program, we aim to uncover the role and mechanism of AQP3 on breast cancer metastasis by using a combination of in vitro cellular systems, clinical breast cancer samples and multiple in vivo metastasis models. We will use high-throughput screening chip to figure out the molecular pathways connecting AQP3 and EMT, and, use Co-IP combined with LC-MS/MS methods to pick out the AQP3-interacting proteins. To investigate whether AQP3 and its effector molecules could be relevant to the metastatic progression of human breast cancer, we will examine their expression patterns in relevant microarray data sets. Furthermore, we will over-express and know-down AQP3 in breast cancer cell lines and examined their ability of metastasis in vivo. Taken together, we will clarify the role and mechanism of AQP3 on breast cancer metastasis and provide potential targets for diagnosis, therapy and prognosis of breast cancer.

多项研究表明AQP3可能在乳腺癌转移过程中存在重要作用。本项目组已发表的成果及前期工作显示，AQP3表达升高后，乳腺癌细胞的迁移、侵袭能力增强，同时会呈现出上皮-间质转换（EMT）的趋势，但其具体机制尚不清楚。本项目将从细胞模型、临床样本和动物模型3个水平深入研究AQP3介导的EMT过程在乳腺癌转移中的作用及其具体机制：高通量筛选并多层面验证AQP3下游影响EMT过程的相关分子及AQP3作用的具体靶点，解析AQP3介导EMT发生的分子机制；利用乳腺癌临床标本，研究AQP3与EMT相关分子在患者癌细胞中表达的相关性，探究它们与患者预后及癌症复发转移之间的关系。利用裸鼠模型，观察裸鼠是否发生肿瘤转移，检测裸鼠是否表现相应的病理及分子指标。本项目可以为乳腺癌转移的分子机制提供新的理论依据，为临床实践中乳腺癌转移的风险评估和靶向治疗提供坚实的理论基础。

多项研究表明，水通道蛋白3（AQP3）可能在乳腺癌转移过程中存在重要作用。本项目以前期研究成果为切入点，以细胞模型、临床样本和动物模型为研究对象，深入剖析AQP3促进乳腺癌转移的具体机制。针对上皮间质转换（EMT）过程，我们选用上皮型乳腺癌细胞系T47D，并成功构建了AQP3稳定高表达细胞系T47D/AQP3+进行研究；在细胞水平进一步明确AQP3对乳腺癌细胞迁移、侵袭的影响。利用裸鼠模型，我们观察到乳腺癌T47D细胞过表达AQP3后在体内更具有侵袭性。高通量蛋白质组学结果显示，AQP3高表达可能会影响肿瘤细胞肌动蛋白通路的调节，从而影响肿瘤细胞的EMT过程及外泌体分泌过程。本项目可以为乳腺癌转移的分子机制提供新的理论依据，为临床实践中乳腺癌转移的风险评估和靶向治疗提供坚实的理论基础。