Dietary habits that can induce inflammatory bowel disease (IBD) are major colorectal cancer (CRC) risk factors, but mechanisms linking nutrients, IBD, and CRC are unknown. Using human data and mouse models, we show that mTORC1 inactivation-induced chromosomal instability impairs intestinal crypt proliferation and regeneration, CDK4/6 dependently. This triggers interleukin (IL)-6-associated reparative inflammation, inducing crypt hyper-proliferation, wound healing, and CRC. Blocking IL-6 signaling or reactivating mTORC1 reduces inflammation-induced CRC, so mTORC1 activation suppresses tumorigenesis in IBD. Conversely, mTORC1 inactivation is beneficial in APC loss-dependent CRC. Thus, IL-6 blockers or protein-rich-diet-linked mTORC1 activation may prevent IBD-associated CRC. However, abolishing mTORC1 can mitigate CRC in predisposed patients with APC mutations. Our work reveals mTORC1 oncogenic and tumor-suppressive roles in intestinal epithelium and avenues to optimized and personalized therapeutic regimens for CRC.

中文翻译：

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mTORC1失活促进结肠炎诱导的大肠癌，但保护免受APC丢失依赖性肿瘤发生。

饮食习惯可以诱发炎症性肠病（IBD），是主要的结直肠癌（CRC）危险因素，但营养物质，IBD和CRC的关联机制尚不清楚。使用人类数据和小鼠模型，我们表明mTORC1失活诱导的染色体不稳定性削弱了肠隐窝的增殖和再生，CDK4 / 6依赖。这会触发白介素（IL）-6相关的修复性炎症，诱导隐窝过度增殖，伤口愈合和CRC。阻断IL-6信号传导或重新激活mTORC1可减少炎症诱导的CRC，因此mTORC1激活可抑制IBD中的肿瘤发生。相反，mTORC1失活在APC丢失依赖性CRC中是有益的。因此，IL-6阻滞剂或富含蛋白质的饮食相关的mTORC1激活可预防IBD相关的CRC。然而，废除mTORC1可以减轻患有APC突变的易感患者的CRC。我们的工作揭示了mTORC1致癌和肿瘤抑制作用在肠上皮中以及为CRC优化和个性化治疗方案的途径。