Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China.
Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, P.R. China.
Int J Oncol. 2016 Jan;48(1):215-24. doi: 10.3892/ijo.2015.3225. Epub 2015 Nov 2.
Chronic inflammation is a well-known etiological factor for colorectal cancer (CRC) and cancer cells are known to preferentially metabolize glucose through aerobic glycolysis. However, the connection between chronic inflammation and aerobic glycolysis in the development of CRC is largely unexplored. The present study investigated whether interleukin-6 (IL-6), a pro-inflammatory cytokine, promotes the development of CRC by regulating the aerobic glycolysis and the underlying molecular mechanisms. In colitis-associated CRC mouse, anti-IL-6 receptor antibody treatment reduced the incidence of CRC and decreased the expression of key genes in aerobic glycolysis, whereas the plasma concentrations of glucose and lactate were not affected. Consistently, IL-6 treatment stimulated aerobic glycolysis, upregulated key genes in aerobic glycolysis and promoted cell proliferation and migration in SW480 and SW1116 CRC cells. 6-phoshofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) was the most downregulated gene by anti-IL-6 receptor antibody in colorectal adenoma tissues. Further analysis in human samples revealed overexpression of PFKFB3 in colorectal adenoma and adenocarcinoma tissues, which was also associated with lymph node metastasis, intravascular cancer embolus and TNM stage. In addition, the effect of IL-6 on CRC cells can be abolished by knocking down PRKFB3 through siRNA transfection. Our data suggest that chronic inflammation promotes the development of CRC by stimulating aerobic glycolysis and IL-6 is functioning, at least partly, through regulating PFKFB3 at early stage of CRC.
慢性炎症是结直肠癌（CRC）的已知病因，癌细胞已知通过有氧糖酵解优先代谢葡萄糖。然而，慢性炎症与 CRC 发展中的有氧糖酵解之间的联系在很大程度上尚未得到探索。本研究探讨了白细胞介素 6（IL-6），一种促炎细胞因子，是否通过调节有氧糖酵解及其潜在的分子机制促进 CRC 的发展。在结肠炎相关的 CRC 小鼠中，抗 IL-6 受体抗体治疗降低了 CRC 的发生率，并降低了有氧糖酵解的关键基因的表达，而血浆葡萄糖和乳酸浓度不受影响。一致地，IL-6 处理刺激有氧糖酵解，上调有氧糖酵解的关键基因，并促进 SW480 和 SW1116 CRC 细胞的增殖和迁移。在结直肠腺瘤组织中，抗 IL-6 受体抗体最下调的基因是 6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶-3（PFKFB3）。对人类样本的进一步分析显示，PFKFB3 在结直肠腺瘤和腺癌组织中过度表达，这也与淋巴结转移、血管内癌栓和 TNM 分期有关。此外，通过 siRNA 转染敲低 PRKFB3 可以消除 IL-6 对 CRC 细胞的作用。我们的数据表明，慢性炎症通过刺激有氧糖酵解促进 CRC 的发展，而 IL-6 通过调节 CRC 早期的 PFKFB3 发挥作用，至少部分如此。
