代谢异常是恶性肿瘤的基本特征。代谢基因或蛋白可通过行使非代谢功能参与肿瘤的发生和发展。NPC1L1是人体胆固醇吸收的关键分子，临床及动物研究发现其抑制剂依折麦布具有致癌风险。我们的前期实验显示NPC1L1在人结直肠癌组织中表达缺失，并与临床病理参数密切相关，NPC1L1敲除促进APCmin/+小鼠肠道肿瘤生成和结直肠癌细胞的恶性表型，初步机制研究表明NPC1L1通过非胆固醇代谢途径调控NF-κB信号通路参与结直肠癌的恶性表型。本项目拟以临床标本、基因敲除小鼠、细胞模型为研究对象，进一步探讨NPC1L1通过招募CYLD去泛素化TRAF2负调控NF-κB信号通路参与结直肠癌发生发展的分子机制。本研究不仅能够丰富对胆固醇转运分子NPC1L1非代谢新功能的认识，为阻断NF-κB信号通路和结直肠癌发生发展提供新的靶点，同时也为解决NPC1L1抑制剂潜在致癌风险的的争议提供可能的实验证据。

Aberrant metabolism is a hallmark of cancer. Metabolic genes and their encoded proteins can participate in tumorigenesis and tumor progression independent of their metabolic functions. NPC1L1 is a major cholesterol transporter and identified as molecular target of ezetimibe, a widely used cholesterol lowing drug worldwide. Clinical trial and experimental data revealed that ezetimibe might have potential cancer-promoting effect, suggesting that NPC1L1 might play important roles in tumorigenesis and tumor progression. Our previous study found an extensive loss of NPC1L1 in colorectal cancer specimens and a close association with clinical characteristics. Evidence from APCmin/+ mice and colorectal cancer cell lines indicated that inactivation of NPC1L1 robustly promoted tumorigenesis and tumor malignancy. Preliminary mechanism study showed that NPC1L1 regulates colorectal tumorigenesis and tumor malignancy through modulating NF-κB signaling independent of its function as cholesterol transporter. Based on the clinical specimens and established NPC1L1 knockout mice and cell lines, this project aims to further investigate the hypothesis that NPC1L1 regulates colorectal tumorigenesis and tumor malignancy as a negative regulator of NF-κB signaling by recruiting deubiquitinase CYLD. This will not only enrich our understanding of NPC1L1 function, but also provide novel targets for blocking NF-κB signaling and colorectal tumorigenesis as well as tumor malignancy. Moreover, these findings may provide experimental evidence for explaining cancer-promoting debates of ezetimibe.