孤儿核受体Nur77在乳腺癌生长和转移中的作用与机制研究

Orphan Nuclear Receptor Nur77 is an important member of the nuclear receptor family, which can be induced by a variety of cytokines and participate in the regulation of cell proliferation, differentiation, apoptosis and autophagy. The abnormal expression or dysfunction of Nur77 can lead to cancer, diabetes, atherosclerosis or other major diseases. Our preliminary studies showed that Nur77 can regulate the growth and tumor immunity of breast cancer, and plays an important role in the progression of breast cancer. We will focus on the use of MMTV-PyMT transgenic mice to study the effect of Nur77 on the growth and metastasis in different stages of breast cancer progression and to explore the molecular mechanism of Nur77 in regulating the growth and metastasis of breast cancer by interacting with the key signaling proteins that control cell growth, invasion and metastasis. In addition, we will use SPR technology to identify new small molecule that targets Nur77 to inhibit the growth and metastasis of breast cancer. This research will provide an important theoretical and experimental basis for in-depth understanding of the evolution of breast cancer and the search for new targets for the treatment of breast cancer.

孤儿核受体Nur77是核受体家族的重要一员，可被多种细胞因子诱导表达，参与调控细胞的增殖、分化、凋亡和自噬等，具有多种生物学功能，其表达和功能异常会导致肿瘤等重大疾病。我们前期研究结果显示Nur77能够调控乳腺癌生长和肿瘤免疫，在乳腺癌发生发展中具有重要作用。本项目利用MMTV-PyMT转基因自发乳腺癌小鼠，重点研究孤儿核受体Nur77在乳腺癌不同发展阶段对肿瘤生长和转移的影响，探索Nur77与控制细胞生长、侵袭与转移的关键信号节点蛋白相互作用调控乳腺癌生长、转移的相关分子机制。此外，利用表面等离子体共振技术鉴定新的靶向Nur77抑制乳腺癌生长和转移的小分子配体。本项目将从全新的视角研究Nur77在乳腺癌生长和转移中的作用，为深入了解乳腺癌演进规律，寻找新的治疗靶点提供重要理论和实验依据。

本项目重点研究了孤儿核受体Nur77在乳腺癌细胞生长、耐药、线粒体调控和重要免疫分子调控中的功能及机制。鉴定了一系列靶向Nur77诱导乳腺癌细胞凋亡的化合物，并探索了作用机制，为基于Nur77的药物开发奠定了基础。主要工作如下：.1. Nur77调控乳腺癌发生发展。MMTV-PyMT模型中敲除Nur77抑制乳腺癌生长；细胞和分子实验结果显示Nur77可能通过与ERα相互作用调控乳腺癌细胞周期进程。.2. Nur77调控乳腺癌细胞他莫西芬耐药。乳腺癌耐药细胞株中Nur77高表达，并通过增强Bcl2和抑制P38信号促进耐药。.3. Nur77调控PD-L1表达。ER阳性乳腺癌细胞Nur77高表达，PD-L1低表达，而三阴性乳腺癌细胞则相反。乳腺细胞中敲除Nur77促进PD-L1表达，进一步的实验显示Nur77可能通过与STAT1相互作用调控PD-L1表达。.4. Nur77调控线粒体分裂。敲除或敲低Nur77后线粒体片段化显著增强，分子和细胞实验显示Nur77通过与Drp1相互作用调控线粒体分裂。.5. 靶向Nur77小分子化合物筛选与活性测试。设计合成了36 个新型氧化 DIM 衍生物，通过Biacore和荧光滴定等实验，结合活性测试，鉴定出一个靶向Nur77且具有很好开发价值的化合物，进一步的实验表明该化合物通过诱导Nur77出核并定位到线粒体上与Bcl2相互作用促进肿瘤细胞凋亡。