Hedgehog（Hh）信号过度活化，与结肠癌等肿瘤的发生发展和耐药密切相关。Gli蛋白是Hh信号通路中的关键转录因子，其泛素化修饰在Hh信号转导中起到重要作用。HOIP是已知的唯一的介导线性泛素化的E3连接酶，但其对Gli的泛素化修饰及在结肠癌中的病理功能未见相关报道。.我们前期研究发现：1）HOIP在结肠癌组织中表达高于癌旁组织；2）HOIP高表达促进结肠癌细胞增殖和耐药；3）HOIP能通过稳定转录因子Gli激活Hh信号。据此提出科学假设：线性泛素连接酶HOIP通过稳定Gli并增强Hh信号，从而促进结肠癌细胞增殖和耐药。.本项目中，我们拟综合利用多学科技术，研究HOIP对Gli蛋白的线性泛素化修饰，构建细胞和动物模型探索HOIP通过Hh信号促进结肠癌细胞增殖和耐药的作用与机制，并通过临床队列分析建立HOIP与结肠癌患者预后的相关性，为结肠癌诊治提供新的靶点。

Aberrant activation of Hedgehog (Hh) signaling firmly relates with the initiation, development and drug resistance in multiple tumors, including colorectal cancer (CRC). Ubiquitination of Gli proteins, the key transcriptional factors in Hh signaling pathway, plays essential role in Hh signaling. HOIP is the only known E3 ligase mediating linear ubiquitination, however, the function of HOIP in mediating the ubiquitination of Gli proteins and facilitating tumorigenesis and drug resistance remains unknown..Our previous data claimed that the expression of HOIP is higher in CRC, compared with the adjacent tissue, and the highly expression of HOIP promotes cell proliferation and drug resistance in CRC cells. Further study revealed that HOIP would activate Hh signaling pathway via stabilizing transcriptional factor Gli..Thus, we hypothesized that HOIP might stabilize Gli through mediating its linear ubiquitination, activate Hh signaling pathway, and facilitate cell proliferation and tumor growth in CRC..Herein, we could, integrating various biochemical and molecular biological methods, investigate the molecular mechanism how HOIP stabilizes Gli via mediating its linear ubiquitination, and regulates Hh signaling pathway in the cellular level. And we would also declare the physical function of HOIP in facilitating tumor growth and drug resistance of CRC in vivo by xenograft model and AOM-DSS induced colon cancer in mice. Furthermore, the relationship between the expression level of HOIP and prognosis of CRC would be generated via clinical cohort..Through this research, we would claim a novel mechanism how Hh signaling is regulated in tumor tissues theoretically, and offer potential targets to CRC diagnosis and therapy.