结直肠癌易发生肝转移影响预后，已有研究提示其发病与肿瘤内多条信号通路异常活化相关。我们研究发现mir-29a在伴有肝转移的结直肠癌组织中高表达，同时体外实验发现mir-29a促进结直肠癌细胞侵袭转移，并调控MMP2，MMP9等转移相关分子。提示mir-29a参与调控结直肠癌肝转移。本研究拟开展：1.临床组织标本中检测mir-29a表达与肝转移及生存期等临床病理特征的关系。2. 筛选mir-29a下游靶基因，研究其下游靶基因对结直肠癌细胞转移能力的调控，寻找新的mir-29a调控靶点3.探索wnt、AKT等信号通路对mir-29a的相互调控机制。明确结直肠癌肝转移中mir-29a失调控机制及其下游调控通路，为治疗结直肠癌肝转移提供潜在的药物靶标。

Liver metastasis is a negetive prognostic factor of colorectal cancer（CRC）. Studies have revealed that abberant signaling pathway contribute to the pathogenesis of metastais. In our previous study, the expression level of mir-29a was found increased in CRC with liver metastasis. In vitro study implicated that mir-29a promote invasion, migration and EMT of CRC cell lines. These resluts indicate that mir-29a regulate the liver metastasis of CRC. In this project, we will 1) Analyses the relationship between mir-29a expression and clinical-pathological features of metastatic CRC. 2) Discovering the target gene of mir-29a and its down-stream mechenism in regulating metastasis. 3)Exploring the regulation between mir-29a and signaling pathway. expecting to identify the role of mir-29a participated in the down-stream regulation processes and the de-regulation mechanism of mir-29ain CRC with liver metastasis.

本研究中，我们发现mir-29a通过抑制其靶基因KLF4，进而调控MMP2，参与了结直肠癌转移过程。结直肠癌中，mir-29a高表达及KLF4低表达提示预后不良。发现粪便mir-29a及mir-224表达是结直肠癌早期诊断指标。研究发现结直肠癌中PHKB是结直肠癌的独立预后因素，其通过P53调控结直肠癌细胞增殖及周期。发现蛋白酶体抑制剂硼替佐米促进泛素化蛋白出核转运，其中包括p53，提示细胞对蛋白酶体抑制剂产生自我保护机制。KPT330阻止泛素化蛋白发生出核转运，增强了蛋白酶体抑制剂对结直肠癌的抗肿瘤作用。P53的核定位以及表达水平升高介导药物协同效应，硼替佐米+CRM1抑制剂联合用药对于p53野生型患者具有较好的治疗效果。