IBP抑制自噬在乳腺癌增殖转移中的作用及机制研究

Breast cancer is one of the major diseases that seriously endangers womens' health. Metastasis is still a big problem in the prevention and treatment of breast cancer. Autophagy plays a crucial role in metastasis, and the elucidation of its underlying concrete mechanism would be of great significance in the improvement of the diagnosis and treatment of breast cancer. Based on the previous discovery that IRF-4 binding protein(IBP) is abnormaly expressed in the breast cancer tissue and promotes its metastasis, our further research found that IBP may inhibit autophagy of breast cancer through the PI3K/Akt/mTOR pathways and have relationship with the proliferation and metastasis of breast cancer cells ,but its mechanism is still unknown. This project intends to adopt the serial molecular biological techniques, such as laser scanning confocal microscope, transmission electron microscope, western blotting, immunofluorescence and in vivo imagine technology. Besides, by way of some cell and animal models such as MTT,breast carcinoma cells xenotransplantation in node mice,invasiveness and migration in vitro, lung colony formation in vivo, and lung metastasis of breast carcinoma cells, we will clarify the relationship between IBP's role in suppressing autophagy and promoting metastasis, and then investigate the underlying mechanisms by which IBP regulates the metastasis of breast cancer. This project aims at improving the understanding of the correlation between the metastasis and autophagy of breast cancer cells in order to provide some new idea and therapeutic targets for the clinical cure of breast cancer.

乳腺癌是严重威胁妇女健康的重大疾病,转移是乳腺癌防治中的一大难题。自噬在乳腺癌增殖转移中发挥重要作用，阐明其中的具体机制对于提高乳腺癌的诊治水平具有重要意义。我们在前期发现IRF-4结合蛋白（IBP）异常高表达于乳腺癌上皮组织并促进乳腺癌增殖转移的基础上，进一步研究发现，IBP可能通过PI3K/Akt/mTOR信号通路抑制乳腺癌细胞自噬发生，且与乳腺癌细胞增殖转移有关，但其机制尚不清楚，有待进一步深入研究。本项目拟采用激光共聚焦、透射电镜、Western Blot、免疫荧光、活体成像等多种技术，通过MTT增殖、小鼠乳垫原位接种、体外迁移与侵袭、小鼠体内肺集落形成、小鼠乳腺癌肺转移等细胞和动物模型，明确IBP抑制自噬与乳腺癌增殖转移的关系，并探讨IBP抑制自噬对乳腺癌增殖转移影响的可能分子机制。本项目将有助于完善对乳腺癌自噬与转移机制的认识，为临床乳腺癌的诊治提供新的思路及靶点。

乳腺癌是严重危害妇女健康的重大疾病，其主要死因源于乳腺癌转移，已成为乳腺癌防治中的一大难题。细胞自噬在乳腺癌细胞增殖转移中发挥重要作用。干扰素调节因子4-结合蛋白(Interferon regulatory factor4-binding protein, IBP) 是在人免疫系统中大量表达并具有参与免疫突触形成和维持免疫内环境稳定等重要功能的蛋白质。本课题组合应用激光共聚焦、透射电镜、Western Blot、免疫荧光等多种技术，以IBP表达不同的乳腺癌细胞株为对象，通过体内、外增殖和转移模型，在研究IBP调节自噬与乳腺癌增殖转移关系的基础上，探讨了IBP调节自噬对乳腺癌增殖转移的作用及其主要分子机制。主要结果：①IBP 抑制乳腺癌细胞自噬；②IBP通过激活mTORC2信号通路抑制乳腺癌细胞自噬；③细胞模型证实IBP抑制自噬促进乳腺癌细胞增殖转移与其激活mTORC2信号通路有关；④动物模型证实IBP抑制自噬促进乳腺癌细胞增殖转移与其激活mTORC2信号通路有关；⑤乳腺癌临床标本证实IBP抑制自噬与其激活mTORC2信号通路有关；⑥激活自噬抑制乳腺癌细胞对紫杉醇的耐药性。结论：IBP具有抑制乳腺癌细胞自噬的作用，IBP抑制自噬与其促进乳腺癌增殖转移有密切关系，IBP激活mTORC2信号通路是其重要机制。本研究结果有助于完善对乳腺癌自噬与增殖转移机制的认识，为临床乳腺癌的诊治提供新的思路及靶点。