TRIP6通过调控肿瘤干细胞促进大肠癌转移的机制研究

在我国，大肠癌死亡率居癌症死亡前列，造成大肠癌死亡的主要原因是肿瘤转移。本团队前期研究发现TRIP6促进大肠癌侵袭及转移。在前期研究基础上，结合最新的大肠肿瘤类器官培养、CRISPR cas9基因编辑技术、条件性基因修饰小鼠和体内示踪体系等多个技术平台，立足于现有对大肠癌CSCs认识的基础，本课题综合研究:1)阐明细胞水平TRIP6对维持大肠癌CSCs干性的生物学功能；2)基于条件性基因修饰小鼠和体内示踪体系，在体水平TRIP6在维持大肠癌干细胞干性中的功能及对大肠癌转移的调控；3)选取来自2个研究中心的大肠癌临床队列，利用大肠癌组织样本评估TRIP6表达水平，明确TRIP6在大肠癌患者体内表达情况及其作为独立的大肠癌预后判断标志物的应用价值；建立TRIP6联合化疗药物5-FU或奥沙利铂治疗大肠癌的类器官和实验动物模型，明确TRIP6的在大肠癌治疗方面的可能的临床价值。

Colorectal cancer (CRC) remains the third most-diagnosed cancer in Europe, the United States and worldwide, about 30% of patients with CRC present with a metastatic disease, which is the leading cause of cancer death. Our previous study had revealed that, TRIP6 promoted colorectal cancer metastasis. In this study, 1) we will elucidate the expression of cell-level TRIP6 in CSCs of colorectal cancer and its biological function in maintaining the dryness of CSCs of colorectal cancer; 2) Based on conditional gene modification in mice and in vivo tracer system , we build TRIP6 knock in/knock out mice, investigeteTRIP6's role and molecular mechanism in maintaining stem cell stemness in colorectal cancer and its regulation of colorectal cancer metastasis were studied in vivo. 3) Finally, we will investigate the prognostic significance of TRIP6 mRNA and protein expression in two different cohorts of colorectal cancer patients. Patient samples have already been collected in our tissue bank, and we will use Q-PCR and immunohistochemistry on tissue microarray to determine TRIP6 expression, respectively and analyze their correlation with clinicopathological parameters. This study will provide important evidence for the functional significance, mechanism of action and clinical implication of TRIP6 in colorectal cancer metastasis.