结直肠癌是常见的消化道肿瘤之一。转移是导致结直肠癌患者死亡的主要原因。目前尚未有防治侵袭转移的有效措施。LKB1缺失会导致Peutz-Jeghers综合征(PJS)的发生，PJS患者有高结直肠癌风险。已有研究报道LKB1的低表达与结直肠癌不良预后相关。我们的预实验结果表明敲除LKB1可促进结直肠癌细胞的转移且与TNIK的表达相关；在AOM/DSS诱导的肠道上皮细胞特异性敲除LKB1小鼠肠道肿瘤中也证实LKB1与TNIK存在负调控关系。目前，关于LKB1通过TNIK调控肿瘤转移的机理尚不明了。本项目在充分前期研究的基础上，将以结直肠癌细胞系、小鼠模型、结直肠癌患者标本为主要研究材料，系统、全面地阐释LKB1负调控TNIK的分子机制以及LKB1/TNIK信号轴调控结直肠癌转移的机制。本项目的实施旨在为诠释结直肠癌转移复发的分子机制提供新的理论依据，也为寻找新的治疗靶点提供重要思路。

Colorectal cancer (CRC) is one of the most malignant tumors in digestive system. Metastasis is a leading cause of death in patients with colorectal cancer. At present, there are no effective measures to prevent invasion and metastasis of CRC. Peutz-Jeghers syndrome (PJS) is an inherited polyposis syndrome and is caused by a germline mutation in the STK11 (LKB1) gene. The cumulative risk for developing gastrointestinal cancer has been estimated to be 70%. Among colorectal cancer patients, low LKB1 tumors exhibited shorter overall survival and relapse free survival periods than high LKB1 tumors. In our preliminary study, we found LKB1-knockout HCT116 cells that established by the CRISPR-cas9 system promoted the metastasis of colorectal cancer cells both in vitro and in vivo and was dependent on the expression of TNIK, and LKB1 could negatively regulate the expression of TNIK in AOM/DSS-induced intestinal-specific LKB1-knockout (Cre+ LKB1+/loxp) mice. However, there is no study demonstrating the mechanism by which LKB1 regulates tumor metastasis through TNIK. In this proposal, we will further explore the molecular mechanism of LKB1 in negatively regulating the expression of TNIK and the mechanism of LKB1/TNIK signaling axis in regulating colorectal cancer metastasis. The clinical significance will also be respectively analyzed. This project aims to increase our understanding of the molecular mechanism of CRC recurrence and metastasis, and also provides important ideas for finding new therapeutic targets.