新相关基因Bmi-1在大肠癌肝转移中的作用及机制研究

项目名称： 新相关基因Bmi-1在大肠癌肝转移中的作用及机制研究

项目编号： No.81472213

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王观宇

作者单位： 浙江大学

项目金额： 52万元

中文摘要： 肝脏是大肠癌最常见的转移器官，目前认为上皮间质转化（EMT）与大肠癌转移有关，但是分子作用机制仍不清楚。我们前期研究发现表观遗传调控因子Bmi-1在大肠癌患者肝转移灶组织中的表达较原发灶组织显著增高，并参与调控大肠癌细胞迁移与侵润，是大肠癌肝转移的新促进因子。本研究拟在前期工作的基础上，观察在肿瘤微环境（低氧、促炎症因子IL-1β刺激）作用下Bmi-1对大肠癌细胞侵袭转移能力及肿瘤细胞干性的影响，并运用EMT PCR Array、western-blot、免疫荧光、特异信号通路阻断等方法研究Bmi-1调控的关键信号通路分子变化，进而通过建立3D培养大肠癌组织模型和大肠癌肝转移裸鼠模型，明确 Bmi-1对大肠癌肝转移的促进作用并探讨其具体作用机制，最后用临床组织标本验证关键分子表达变化，从而为探索大肠癌肝转移的发病机制和找到新的治疗靶点奠定基础。

中文关键词： C08_结；直肠肿瘤；Bmi-1；肝转移；上皮间质转化

英文摘要： Liver is the most common metastatic site for colorectal cancer (CRC).Though studies show that the epithelial-mesenchymal transition (EMT) is one of the main mechanisms underlying development of CRC metastasis, the exact molecular mechanisms remain unclear. Clinically, we found that the polycomb-group protein Bmi-1 was higher expressed in a cohort of human hepatic metastasis than in their primary colorectal tumors, suggesting that it might play an important role in mediating CRC liver metastasis. Our preliminary results also showed that Bmi-1 promoted mitigation and invasion abilities in CRC cells. In this study,we aim to investigate the role of Bmi-1 in regulating metastasis ability in CRC cells and stemness in cancer stem cells under hypoxia or inflammatory cytokine IL-1β treatment. Then the genes and proteins that are functionally critical under Bmi-1 regulation will be identified using EMT PCR array, Western-blot assay, spheroids formation assay, immunofluorescence analysis ect. Furthermore, 3D Organotypic raft culture and nude mice models of experimental CRC liver metastasis will be used to confirm what we find above. In addition,we will collect samples from CRC patients with/without liver metastasis for primary culture of tumor cells and tissue immunohistochemistry to confirm the molecular mechanisms. These findings will shed a new light on understanding molecular mechanisms underlying colorectal cancer liver metastasis and provide a potent molecular target for treatment.

英文关键词： colorectal cancer;Bmi-1;liver metastasis;epithelial-mesenchymal transition