Calponin 2通过调控巨噬细胞参与结肠炎相关结肠癌发生发展机制的研究

IBD is identified as a complex, remitting and relapsing inflammatory disorders that affecting the intestinal tract, with genetic and environmental risk factors. A serious consequence of long-term chronic inflammation is an increased risk of tumorigenesis. However, the exact pathogenesis of colitis associated cancer(CAC) is not fully understood. Applicant have found that macrophages and other monocytes have played an important role in inflammation-induced tumorigenesis (first author, Cancer Cell, 2013). Previous studies had proved that Calponin 2 participated in inflammatory response by inhibiting macrophage activation, and applicant found that Calponin 2 involved in the pathogenesis of GI cancer (Corresponding Author, Oncotarget，2017).In this study, we aim to investigate the mechanism of how Calponin 2 affect colitis and CAC by regualting colonic epithelial cells and immune cell, especially macrophage, and propose the possible methods of clinical intervention.

IBDs 是多种病因引起的、异常免疫介导的肠道慢性、复发性炎症，长期慢性炎症增加肿瘤发生的风险，然而IBDs 癌变的确切机制尚不明确。申请人前期发现巨噬细胞等单核细胞在炎症诱导肿瘤中发挥了重要作用(第一作者,Cancer Cell,2013)，课题组前期研究提示 Calponin2可以调控巨噬细胞活化参与炎症反应，且申请人近期研究证实Calponin2参与消化系肿瘤的恶性生物学行为(通讯作者,Oncotarget,2017)。本课题拟结合临床标本、动物模型及细胞学实验，利用Calponin2-/-和对照小鼠的结肠炎、结肠炎相关性结肠癌动物模型，研究 Calponin2对结肠上皮细胞、免疫细胞的调控，特别是通过调控巨噬细胞，影响结肠炎和结肠炎相关结肠癌的发生发展，明确Calponin2参与消化系肿瘤发生发展的机制，为临床防治提供干预手段。

炎症性肠病在我国发病率逐年增高，随着患病时间的延长，结肠炎相关结肠癌的发生率进一步升高，影响我国人民生活健康。寻找结肠炎及结肠炎相关结肠癌的靶点和深入机制研究具有重要意义。本课题的资助下，按照计划书内容顺利进行，已完成课题，发现：（1）在炎症性肠病患者外周血单核细胞中，H2-Calponin表达量显著下调；（2）DSS诱导小鼠构建急性、慢性结肠炎模型，与WT小鼠相比，H2-Calponin-/-小鼠肠道组织破坏程度和炎症浸润程度明显加重；（3）H2-Calponin表达下调促进巨噬细胞介导的IL-6分泌和NF-κB信号转导通路的激活；（4）H2-Calponin表达下调促进炎症相关结肠癌的发生、发展。从而为炎症性肠病和结肠炎相关结肠癌的治疗靶点提供依据。本项目支持下同时带本项目基金号已发表SCI论文11篇，中文论文3篇。参与制定国内指南7部，国际会议特邀报告2次，国内会议特邀报告、壁报5次，培养6名博士研究生、3名硕士研究生顺利毕业。在读培养博士研究生3名，硕士研究生4名，博士后1名。