title: Interleukin-6 stimulates aerobic glycolysis by regulating PFKFB3 at early stage of colorectal cancer.
abstract: 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.
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China.
authors.forename: Qingyang
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China.
authors.forename: Qiulei
authors.initials: Q
authors.lastname: Xi
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, P.R. China.
authors.forename: Yongxian
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China.
authors.forename: Qiulin
authors.initials: Q
authors.lastname: Zhuang
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China.
authors.forename: Yusong
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, P.R. China.
authors.forename: Qiurong
authors.initials: Q
authors.lastname: Ding
authors.affiliation: Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, P.R. China.
authors.forename: Guohao
authors.initials: G
authors.lastname: Wu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009367:Neoplasm Staging; D025481:Phosphofructokinase-2 / Q000096:biosynthesis* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D015850:Interleukin-6; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2