苦木调控FXR-NF-κB/IL-6/STAT3通路干预结肠炎-癌转化的作用机制研究

FXR是干预结肠炎-癌转化的潜在靶点，起抑制炎症微环境、癌细胞增殖和调控胆汁酸稳态作用。NF-κB介导IL-6/STAT3通路释放凋亡相关因子促进细胞异常增殖，而FXR与NF-κB相互拮抗。前期研究显示中药苦木活性成分苦木碱F有效缓解结肠炎，其机制涉及激活FXR抑制NF-κB信号和调控胆汁酸内稳态，并且苦木碱F具有抑制结肠癌细胞增殖的潜力。因此，本项目提出以下科学假说：苦木碱F可能通过激活FXR抑制NF-κB/IL-6/STAT3信号介导的细胞异常增殖，从而干预结肠炎-癌转化病理进程。本项目拟采用TGF-β1诱导肠上皮恶性转化细胞、结肠癌细胞和AOM/DSS诱导的小鼠，从细胞和整体动物水平评价苦木碱F干预结肠炎-癌转化的作用和分子机制，阐明苦木碱F能否调控FXR抑制NF-κB/IL-6/STAT3炎-癌转化信号通路干预结肠炎-癌转化病理进程，为结肠炎-癌防治提供新的治疗策略和药物开发思路。

FXR, a potential target to inhibit the transformation from colitis to colorectal carcinoma, plays an important role in inhibiting inflammation and proliferation of cancer cells, and regulation the homeostasis of bile acid. Ramulus et Folium Picrasmae, commonly called “Kumu” in Chinese, has effects of anti-inflammation and anti-tumor. The effect of its active component 5-Hydroxy-4-methoxycanthin-6-one (PQ-A) on IBD is related to the regulation of bile acid metabolism homeostasis and inflammatory response via FXR and NF-κB. Meanwhile, PQ-A has effects on anti-tumor. This project proposed the scientific hypothesis that “PQ-A may interfere with the transformation from colitis to colorectal carcinoma via FXR-NF-κB/IL-6/STAT3 signaling pathway”. This study uses TGF-β1-induced NCM460 cell, colon cancer cells, and AOM/DSS-induced animals to investigate the pharmacodynamics characteristics and mechanism of PQ-A on colitis-colorectal carcinoma transformation. It hopes to clarify whether PQ-A interferes with the transformation of colitis-colorectal carcinoma via FXR-NF-κB/IL-6/STAT3 signaling pathway.