Abnormal Circadian Clock Ｐromotes AOM / DSS-induced Colon Carcinogenesis in Mice by Remodeling Tumor Metabolism / 中国生物化学与分子生物学报

ABSTRACT

Abnormal circadian clock has been identified as an independent risk factor for tumorigenesis, and is closely related to the occurrence and development of tumor. As metabolic disorder is also one of the important characteristics of tumorigenesis, therefore it is particularly important to investigate the regulatory relationship between biological clock and tumor metabolism. In this study, the effect of abnormal circadian clock on colon cancer growth was evaluated by azoxymethane (AOM) / dextran sodium sulfate (DSS) -induced colitis-associated carcinogenesis (CAC) mice model. The result showed that abnormal circadian clock aggravated anal swelling, redness, bloody and anorectal prolapse in CAC mice, and significantly increased the number and volume of CAC polyps (P <0. 05 or P <0. 01), and reduced the intestinal length, body weight, survival rate of CAC mice and the expression levels of inflammatory factors IL-1β (interleukin-1 beta) and TNFα (tumor necrosis factor α) (P < 0. 05 or P < 0. 01), indicating that abnormal biological clock promotes the occurrence and development of CAC. Further, non-target metabonomics analysis of serum samples from mice was performed by liquid chromatography-mass spectrometry (LC-MS) . The result showed that compared with CAC mice with normal circadian rhythm, 27 differential metabolites were identified in CAC mice with disrupted circadian clock, and 9 metabolic pathways were enriched by KEGG (kyoto encyclopedia of genes and genomes) database. These results suggest that abnormal circadian clock can significantly change the relative abundance of some metabolites in serum samples from CAC mice, remodel tumor metabolism, and result in the development of CAC in mice. This study reveals the pivotal role of tumor metabolism in the abnormal circadian clock promoting the growth of CAC in mice, providing a new experimental basis for the interaction between circadian clock and metabolic homeostasis in the occurrence and development of colon cancer.