ZEB1调控乳腺癌血管生成的功能研究

Growth and metastasis of breast cancer rely on tumor angiogenesis, which is regulated by a variety of active substances. Among these regulatory factors, VEGF exhibits a strong and highly specific effect to promote breast cancer angiogenesis. It has been indicated that the abnormal expression of VEGF is contolled by genes in breast cancer cells. However, the pathological mechanism underlying this regulation remains largely obscure, resulting in a significant limitation and reduction of the efficacy of anti-angiogenic therapy in breast cancer. Our preliminary data indicated a potential role of ZEB1 to induce breast cancer angiogenesis by regulating a variety of angiogenic factors, such as VEGF, etc. Consequently, this project is proposed (1) to study the mechanism by which ZEB1 induces breast cancer angiogenesis via the regulation of VEGF, etc.; (2) to elucidate the correlation between ZEB1 and breast cancer angiogenesis in clinical cases; (3) to investigate the in vivo function of ZEB1 to regulate breast cancer angiogenesis using transgenic mouse models. This project will help to reveal the role of ZEB1 in the regulation of tumor angiogenesis in breast cancer, providing a novel strategy for the prevention and treatment of breast cancer, especially for the individualized prevention and treatment of breast cancer.

乳腺癌生长和转移需要依赖血管生成，受到诸多活性物质调控，其中VEGF是作用较强且特异性高的一种血管生成促进因子。乳腺癌中VEGF的异常表达受到肿瘤细胞内基因的调节，但其具体调控因素和病理机制等尚不完全明确，极大地限制了抗血管生成在肿瘤治疗中的应用。我们的前期研究显示，转录因子ZEB1能够影响VEGF等调节因子的表达，显著促进乳腺癌血管生成。本项目拟在此基础上，（1）深入研究ZEB1调控VEGF等表达的分子机理和信号转导途径等，揭示ZEB1促进乳腺癌血管生成的病理机制；（2）分析ZEB1与VEGF、肿瘤微血管密度MVD等因素在乳腺癌临床标本中表达的相关性，获取可靠的临床数据；（3）利用转基因动物模型，全面分析ZEB1及其不同功能结构域调控乳腺癌血管生成的在体作用。本项目有助于深入阐明ZEB1促进乳腺癌血管生成的病理机制，为乳腺癌防治特别是尽快实现乳腺癌个体化预防与治疗这一关键环节提供新策略。

乳腺癌生长和转移需要依赖血管生成，受到诸多活性物质调控，其中VEGF是作用较强且特异性高的一种血管生成促进因子。乳腺癌中VEGF的异常表达受到肿瘤细胞内基因的调节，但其具体调控因素和病理机制等尚不完全明确，极大地限制了抗血管生成在肿瘤治疗中的应用。我们的前期研究显示，转录因子ZEB1能够影响VEGF等调节因子的表达，显著促进乳腺癌血管生成。所以在本项目的研究中，我们通过体内体外等一系列的实验证实，在乳腺癌中ZEB1 可以上调VEGFA基因mRNA和蛋白的表达，促进VEGF的分泌。这种促进作用主要通过 PI3K 和p38通路实现。Sp1 结合位点是 VEGF 启动子活性的重要影响因子，ZEB1通过募集更多的 Sp1 至 VEGFA启动子上发挥促进调控作用。并且，通过对128例乳腺癌癌组织标本的分析，也证实了ZEBl与VEGFA的表达、ZEBl与CD31的表达均具有显著的正相关性。临床组织标本的统计分析结果进一步支持了我们的实验结论。最后，通过基质凝胶塞和体内成瘤等动物实验，进一步的证实了ZEB1能够促进血管的新生，促进乳腺癌的发生。本项目深入阐明了ZEB1促进乳腺癌血管生成的病理机制，为乳腺癌防治特别是尽快实现乳腺癌个体化预防与治疗这一关键环节提供新策略。