基于STAT3/c-Myc通路探讨川楝素调控代谢重编程防治肠炎相关性结肠癌（CAC）的作用及机制

Colon cancer is one of the most common malignant gastrointestinal tumors. The primary treatment strategy of colon cancer is inhibiting inflammation–cancer progression. Previous studies have found that chronic inflammatory stimulation could induce metabolic reprogramming, which mediates colitis-associated colon cancer (CAC) via STAT3/c-Myc signal pathway. Our research group also found that traditional Chinese herb toosendanin which has potential tumor suppressor activity significantly decreased the activity of LDH-A，Glut-1 and HK2 as well as the expression of STAT3. Considering these, we hypothesized that toosendanin could reduce the level of inflammation by inhibiting STAT3-mediated metabolic reprogramming and then inhibit the progression from inflammation to cancer. Via DSS and TNBS induced colitis mice model and DSS/AOM induced colitis-cancer mice model, this study intends to focus on the regulatory effects of toosendanin on STAT3/c-Myc signaling pathway mediated metabolic reprogramming and the evolution of chronic colitis to colon cancer and explore the potential action target of toosendanin in the anti-inflammation and anti-cancer progress, which will provide experimental basis for traditional Chinese herb’s role in inflammation or cancer evolutionas well as TCM method for early prevention and treatment of colitis associated colon cancer.

肠炎相关性结肠癌（CAC）是临床常见难治性疾病，阻断炎-癌转化是其治疗关键。文献报道及本研究前期证实，持续的炎症刺激可激活STAT3/c-Myc信号通路诱发细胞代谢重编程，促进肿瘤发生。目前，中医药对于CAC的防治取得较好疗效，调气是其重要着眼点。课题组预实验发现，在小鼠慢性结肠炎模型中，理气中药川楝子的抑癌活性组分川楝素能显著减缓其炎症程度，抑制代谢关键酶LDH-A，Glut-1和HK2的活性，并下调STAT3的磷酸化。据此，我们推测：川楝素能通过STAT3/c-Myc信号通路抑制代谢重编程减轻炎症程度，进而阻断结肠炎-癌转化。本研究拟通过体外细胞实验和动物实验，明确川楝素在STAT3/c-Myc信号通路介导的代谢重编程中的作用，并探索其阻断炎-癌转化的机制，为川楝素用于早期防治CAC提供科学依据。

结肠癌是人类最常见的消化道恶性肿瘤之一，约1/4的患者其发病机制与慢性炎症相关。阻断炎-癌转化是肠炎相关性结肠癌（CAC）治疗的核心策略之一，寻找调控结肠炎-癌转化的信号通路及药物是目前研究的热点与难点。本研究首先基于STAT3/c-Myc信号通路介导CAC的调控，采用筛选获得的强抑癌活性先导化合物川楝素进行药效及机制探讨。基于现有研究结果并结合文献研究发现：川楝素可以有效减缓CAC小鼠模型的进程，在离体及在体水平对结肠癌具有确切抑癌活性。并通过建立的小鼠慢性结肠炎及肠炎相关性结肠癌模型，评估了川楝素减缓肠道炎症反应及肠道上皮恶性转化的作用，借助组学研究手段并重点探索了其影响代谢重编程的潜在机制，为川楝素用于肠炎相关性结肠癌的治疗提供了证据。