黏蛋白MUC21/JNK/ZEB1信号轴促进胰腺癌神经转移机制及靶向示踪的研究

胰腺癌易侵犯神经（PNI），常导致顽固性疼痛和术后复发转移，目前缺乏有效识别和治疗手段。我们预实验显示：黏蛋白MUC21依赖JNK上调转录因子ZEB1，既诱导EMT促进转移，又上调神经营养因子受体GFRα1增加神经趋化；敲低ZEB1可拮抗MUC21作用，提示胰腺癌可能存在MUC21上调ZEB1促进其神经转移。同时，抗MUC21抗体特异识别受累神经，可能是PNI诊疗新靶点。本项目拟：①用多个胰腺癌细胞系，进一步明确MUC21激活JNK上调ZEB1及其机制、ZEB1如何调控GFRα1；②细胞和动物水平进一步明确MUC21/JNK/ZEB1信号轴促胰腺癌PNI作用；③构建MUC21靶向分子探针，在鼠移植瘤模型实现多模态示踪，探讨术前显影和术中可视化导航胰腺癌精准手术切除的应用和疗效价值。本项目完成将阐明MUC21促进胰腺癌PNI的分子机制和临床意义，为胰腺癌神经转移诊断和治疗提供新思路、新技术。

Perineural invasion (PNI) often occurs in pancreatic cancer, leading to intractable abdominal pain, postoperative recurrence and metastasis. At present, there is still lack of effective means to identify or treat nerve-invading cancer cells. Our pre-experimental results showed that mucin21 (MUC21) upregulated ZEB1 via JNK signal pathway and enhanced migration and invasion by inducing EMT. MUC21 increased ZEB1 expression also resulted in upregulation of neurotrophin receptor GFRα1, which enhanced the chemotactic ability of pancreatic cancer cells towards nerves. After knocking down ZEB1 by siRNAs, the MUC21-induced upregulation of EMT and GFRα1 was attenuated, suggesting that there may be a MUC21/ZEB1 axis promoting pancreatic cancer cells PNI. In the pre-experiment, we also found that anti-MUC21 antibodies specifically recognized the nerves invaded by pancreatic cancer cells, suggesting that MUC21 may be a new target for the diagnosis and treatment of PNI. The purpose of this project is : ① by use of multiple pancreatic cancer cell lines, to further research the mechanism of MUC21/JNK/ZEB1 axis, including how MUC21 activates JNK, how JNK activation upregulates ZEB1, and how ZEB1 modulates GFRα1 expression. ② to further observe the effect of MUC21/JNK/ZEB1 axis on promoting pancreatic cancer cells PNI both in vitro and in vivo. And, ③ to construct a MUC21-targeting molecular probe which could exert multimodal imaging of PNI in mice allograft bearing human pancreatic cancer cells. We will explore the application and therapeutic value of preoperative imaging and intraoperative visual navigation in precision surgical resection of pancreatic cancer by use of MUC21-targeting nano probe. The completion of this project will clarify the mechanism and clinical significance of MUC21 in promoting PNI in pancreatic cancer, and provide new ideas and new techniques for the diagnosis and treatment of pancreatic cancer with perineural invasion.