microRNA-26a介导肝癌细胞与肿瘤相关巨噬细胞之间的相互对话

项目名称： microRNA-26a介导肝癌细胞与肿瘤相关巨噬细胞之间的相互对话

项目编号： No.81472224

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： 孙惠川

作者单位： 复旦大学

项目金额： 90万元

中文摘要： 肝癌的药物治疗严重缺乏，研究肝癌的生物学特性有助于发展新的治疗策略。我课题组的前期研究发现：肿瘤细胞内microRNA-26a（miR-26a）低表达与NF-κB、IL-6等炎症因子激活相关；癌周巨噬细胞浸润与肝癌侵袭转移相关；两者均为预后不良的标志。因巨噬细胞为NF-κB/IL-6炎症通路激活的主体，肝癌细胞与巨噬细胞间可能通过miR-26a相互联系。预实验中：肝癌细胞miR-26a表达降低可促进巨噬细胞募集并出现促肿瘤的M2表型；巨噬细胞反过来可抑制肝癌细胞miR-26a表达，两者间形成正反馈循环。我们推测，miR-26a在两种细胞的相互对话（cross talk）中处于核心地位。我们拟借助蛋白芯片和ChIP等技术，验证该假说并研究相互对话的机制，寻找调控miR-26a表达的关键转录因子及受miR-26a调控的下游关键靶基因，寻求潜在可干预的靶点以打破相互对话，为药物治疗提供新思路。

中文关键词： C09_肝和肝内胆管肿瘤；微环境；巨噬细胞；microRNA-26a

英文摘要： There're inadequate drug therapies for hepatocellular carcinoma. The study of the cell biology of the hepatoma cells could help to develop of new therapies. In our previous study, we found that low expression of microRNA-26a (miR-26a) was associated with abnormal activation of the inflammatory factors, e.g. NF-κB and IL-6; and peritumoral infiltration of macrophages was associated with tumor invasion and metastasis; both low expression of miR-26a and macrophages infiltration were associated with poor prognosis after surgery. As macrophages were the main entities in which NF-κB/IL-6 pathway was activated, we hypothesized that hepatoma cells and macrophages may be linked via miR-26a. In our preliminary experiments, reduced expression of miR-26a in hepatoma cells enhanced the recruitment of macrophages and induced the macrophages to polarize into tumor-promoting M2 phenotype; inversely, macrophages could down-regulate the expression of miR-26a in hepatoma cells. We hypothesized that there's a cross talk between hepatoma cells and macrophages, and miR-26a may plays a crucial role in this cross talk. In this proposal, we will verify this hypothesis and study the molecular mechanisms of this cross talk. We planned to find the key transcription factor regulating miR-26a expression and the find the key target genes of miR-26a using protein microarray, ChIP assays and etc. By sort for the crucial factors in the cross talk, this study may provide new clues in the development of drug therapies for hepatocellular carcinoma.

英文关键词： hepatocellular carcinma;microenvironment;macrophages;microRNA-26a