Wnt信号通路
结直肠癌
昼夜节律
杂合子丢失
生物钟
生物
时钟
类有机物
癌症研究
生物信息学
癌症
遗传学
内分泌学
基因
等位基因
作者
Sung Kook Chun,Bridget M. Fortin,Rachel C. Fellows,Amber N. Habowski,Amandine Verlande,Wei A. Song,Alisa L. Mahieu,Austin E. Y. T. Lefebvre,Jason N. Sterrenberg,Leandro M Velez,Michelle A. Digman,Robert A. Edwards,Nicholas R. Pannunzio,Marcus M. Seldin,Marian L. Waterman,Selma Masri
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2022-08-12
卷期号:8 (32)
被引量:26
标识
DOI:10.1126/sciadv.abo2389
摘要
An alarming rise in young onset colorectal cancer (CRC) has been reported; however, the underlying molecular mechanism remains undefined. Suspected risk factors of young onset CRC include environmental aspects, such as lifestyle and dietary factors, which are known to affect the circadian clock. We find that both genetic disruption and environmental disruption of the circadian clock accelerate Apc- driven CRC pathogenesis in vivo. Using an intestinal organoid model, we demonstrate that clock disruption promotes transformation by driving Apc loss of heterozygosity, which hyperactivates Wnt signaling. This up-regulates c-Myc , a known Wnt target, which drives heightened glycolytic metabolism. Using patient-derived organoids, we show that circadian rhythms are lost in human tumors. Last, we identify that variance between core clock and Wnt pathway genes significantly predicts the survival of patients with CRC. Overall, our findings demonstrate a previously unidentified mechanistic link between clock disruption and CRC, which has important implications for young onset cancer prevention.
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