髓样分化蛋白2在结肠癌发生发展中的作用机制研究

It is proved that inflammation plays an important role in the development of colon cancer. Myeloid differentiation 2 (MD-2) is an important accessory protein in LPS-TLR4 inflammatory signaling pathway. TLR4/MD-2 complex is the direct mediator in endotoxin (LPS)-induced inflammation. It is found that the constitutive activation of TLR-4 augments inflammatory responses to mucosal injury and promotes proliferation and migration of colon cancer cells. However, whether MD-2 plays a role in this pathology is yet unkown. In our previous studies we found that MD-2 specific inhibitor and MD-2 neutralizing antibody significantly inhibited the proliferation, migration, and infiltration of colon cancer cells. Furthermore, MD-2 specific inhibitor markedly prolonged the survival of the mice with colon cancer. All these data show that MD-2 may be involved in the development of colon cancer via an inflammatory promoting pathway. In this study, we are going to investigate the role of MD-2 in the develepment of colon cancer by using MD-2 knockout mouse, RNA silient technology, MD-2 specific inhibitors, and clinical colon cancer samples. Completion of this challenge project not only has high scientific impact on understanding the MD2-involved mechanism in the development of colon cancer, but also provides new target and strategy for the treatment.

炎症在结肠癌发生、发展和转移等过程中有重要作用。髓样分化蛋白2（MD-2）是LPS-TLR4炎症信号通路的重要辅助蛋白，它协助LPS与TLR4结合，从而激活TLR-4。近年来，TLR-4信号通路的持续激活已被证实促进结肠上皮细胞的癌变、肿瘤细胞的增殖以及迁移。但是该过程是否需要MD-2的参与尚不清楚，MD-2在结肠癌中的作用尚未被阐明。本实验室前期以特异性MD-2抑制剂作为工具药物，发现抑制剂及MD-2中和抗体均能有效抑制结肠癌细胞的体外增殖、迁移与浸润。而且MD-2抑制剂有效延长结肠癌小鼠的生存率，提示MD-2可能通过调节炎症介导结肠癌的发生发展。本项目中，我们拟利用MD-2敲除小鼠、RNA干扰、特异性抑制剂、临床样本等，在细胞、动物和人体多个层面，深入阐明MD-2参与介导结肠癌发生、发展和转移的作用及机制，明确MD-2可以作为结肠癌治疗的重要靶点，为研发新的结肠癌治疗药物提供新靶点。

炎症在结肠癌发生、发展和转移等过程中有重要作用。髓样分化蛋白2（MD-2）是LPS-TLR4炎症信号通路的重要辅助蛋白，它协助LPS与TLR4结合，从而激活TLR4。近年来，TLR4信号通路的持续激活已被证实促进结肠上皮细胞的癌变、肿瘤细胞的增殖以及迁移。但是该过程是否需要MD-2的参与尚不清楚，MD-2在结肠癌中的作用尚未被阐明。本项目中，我们利用MD-2敲除小鼠、RNA干扰、特异性抑制剂、临床样本等，在细胞、动物和人体多个层面，深入阐明MD-2 参与介导结肠癌发生、发展和转移的作用及机制，我们的研究表明：1）MD-2在多种结肠癌细胞系、结肠癌患者肿瘤组织中高表达；2）MD-2促进结肠癌细胞的迁移与浸润；3）MD-2可在体内促进结肠癌的肺转移；4）MD-2可调控肿瘤微环境中巨噬细胞向M2型转化，促进结肠癌向结肠癌发展；5）MD-2促结肠癌转移、促炎癌转化的作用是通过激活NF-κB通路实现的。我们的研究明确了MD-2可以作为结肠癌治疗的重要靶点，为研发新的结肠癌治疗药物提供新靶点。