结直肠癌（CRC）是发病率高、侵袭性强的恶性肿瘤。而神经纤毛蛋白NRP1参与CRC恶性进展，和其不良预后密切相关，但机理有待研究。我们前期工作报道了两个NRP1剪接异构体NRP1-ΔE4和NRP1-ΔE5，发现其能通过持续激活FAK/p130Cas通路而促进CRC转移。最近我们通过高通量测序发现了1个新的NRP1剪接异构体，克隆和测序发现该新剪接异构体通过第4个外显子跳跃（ΔE4，即Δ144-219）和第11个外显子部分序列缺失（Δ615-621）形成，特征性造成N150 N-连接 和S612 O-连接糖基化功能同时缺陷。预实验表明该新剪接异构体能促进CRC细胞迁移和侵袭，其机制是否和N150/S612糖基化缺陷有关？本项目拟从细胞、动物、患者三个层次系统阐明糖基化缺陷的NRP1-Δ144-219&Δ615-621新剪接异构体调控CRC转移的功能和机制，有望为结肠癌的临床治疗提供新思路。

Colorectal cancer (CRC) is one the most common malignant tumors and it is featured with high invasiveness and metastasis that leads to poor outcomes. But it is not well known for the underlying mechanisms. Neuropilin-1(NRP1) is a type I transmembrane protein with non-tyrosine kinase activity and it co-activates oncogenic signaling transduction along with tyrosine kinases such as c-Met, VEGFR and EGFR. NRP1 plays a critical role in CRC progression and metastasis but the mechanism remains to be studied. We recently reported two NRP1 splice variants NRP1-ΔE4 and NRP1-ΔE5 and found that they promoted CRC metastasis by continuously activating the FAK / p130cas pathway. More recnetly, We identified another novel NRP1 splice variant by high-throughput sequencing. This novel NRP1 splice variant was formed via splicing mechanism by skipping Exon 4 (ΔE4， orΔ144-219 a.a.) and lacking a partial sequence (Δ615-621a.a.)in Exon 11.Consequently,it was characterized by simultaneous defect of N-linked glycosylation on N150 and O-linked glycosylation on S612.Our preliminary studies showed that this novel NRP1 splice variant promotes migration and invasion in CRC cells. Given the significance of glycosylation in modulating proteins and cancer metastasis, the present proposal will clarify the functions and mechanisms of novel NRP1-Δ144-219&Δ615-621 splice variants, specifically the N150/S612 glycosylation,on CRC invasiveness and metastasis, from various CRC models of cell lines, nude mics, as well patients' tissue specimens. This study will help understanding of NRP1 and its role in CRC, and it will be hopeful to provide new ideas for CRC treatment.