NOR1与β-catenin相互作用抑制鼻咽癌上皮间质变和侵袭转移的分子机制

NOR1是我室自主克隆的抑瘤基因，在鼻咽癌中表达显著下调。在鼻咽癌细胞中稳定表达NOR1引起细胞形态、细胞骨架改变，抑制上皮-间质变（EMT）分子Slug、vimentin mRNA和蛋白表达。NOR1蛋白并不能作为转录因子直接调节基因的表达，其抑制Slug等分子 mRNA表达的机制不明。Slug是Wnt/β-catenin通路的靶基因。我们发现NOR1与β-catenin存在交互作用，抑制β-catenin蛋白表达和入核，但不影响其mRNA水平。我们推测NOR1通过结合β-catenin，影响其蛋白翻译后修饰，促进其降解，从而抑制Slug转录、EMT和侵袭转移。本项目拟进一步研究NOR1在鼻咽癌侵袭转移中的作用，深入解析NOR1与β-catenin交互作用对Wnt/β-catenin信号通路、EMT及鼻咽癌恶性生物表型的影响和分子机制；解析NOR1发挥上述作用所需蛋白结构域。

Oxidored-nitro domain containing protein 1 (NOR1) is a novel member of the nitroreductase family and a putative tumor suppressor gene. Overexpression of NOR1 in NPC cells resulted in a significant morphological change and decreased expression of epithelial-mesenchymal transition (EMT) inducers (e.g., slug and vimentin), but induced cytokeratin 13 expression. However, the mechanism of NOR1 in EMT is unknown. Wnt/β-catenin pathways are involved in EMT and activated in nasopharyngeal carcinoma. NOR1 interactes with β-catenin protein in NPC cells and decreases β-catenin protein level. We hypothesize that NOR1 modulates the β-catenin post-translational modification and promotes its degradation by binding to β-catenin, thus inhibits EMT and invasion. This project will further study how NOR1 functions in Wnt/β-catenin signaling pathways and EMT in NPC cells. Delete mutants would be constructed and used to deciphering the protein domains required for NOR1-β-catenin interaction.