Prevention of colitic cancer by IL-6 trans-signaling inhibitors

结肠癌是一种大肠癌，发生在一种长期存在的炎症性肠道疾病中。IL-6/STAT3通路在结肠癌发生发展中的作用尚不完全清楚。本研究旨在探讨IL-6反式信号在结肠癌发生发展中的作用。用葡聚糖硫酸钠(DSS)诱导BALB/c小鼠慢性结肠炎。通过对结肠炎感染的小鼠进行额外的DSS治疗来诱发结肠癌。IL-6在受结肠炎和结肠癌影响的小鼠的结肠中表达增加，并且这种表达仅限于固有层巨噬细胞。结肠炎组织中巨噬细胞IL-6R和TACE表达增加，可溶性IL-6R表达增加。相反，在结肠炎和结肠癌小鼠的结肠上皮细胞中，IL-6R的生成减少，并与gp130和磷酸化STAT3的表达增加有关。应该注意的是，可溶性gp130Fc的预治疗显著减少了结肠中的肿瘤形成。巨噬细胞来源的IL-6/可溶性IL-6R诱导上皮细胞的IL-6反式信号转导在结肠癌的发生发展中起重要作用。可溶性gp130Fc对结肠癌的预防可能是有效的。

Colitic cancer is a large bowel cancer that occurs in a long-standing inflammatory bowel disease. The role of the IL-6/STAT3 pathway in the development of colitic cancer has not been fully understood. This study was conducted to investigate whether IL-6 trans-signaling contributes to the development of colitic cancer. Chronic colitis was induced by dextran sodium sulfate (DSS) to BALB/c mice. Colitic cancer was induced by additional DSS treatment to colitis-affected mice. IL-6 expression increased in the colon of colitis- and colitic cancer-affected mice, and this expression was restricted to lamina propria-macrophages. Both IL-6R and TACE expressions increased in macrophages in colitis tissue, and soluble IL6R was increased in these tissues. In contrast, IL-6R generation was reduced in the colonic epithelial cells in colitis- and colitic cancer-mice and was associated with increased expression of gp130 and phospho-STAT3. It should be noted that pre-treatment of soluble gp130Fc significantly reduced the tumorigenesis in the colon. IL-6 trans-signaling in epithelial cells, induced by macrophage-derived IL-6/soluble IL-6R, plays a crucial role in the development of colitic cancer. Soluble gp130Fc may be effective for the prevention of colitic cancer.