Department of Gastroenterology and Hepatology, General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin Medical University, Tianjin, China.
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China.
Cancer Sci. 2022 Feb;113(2):459-477. doi: 10.1111/cas.15208. Epub 2021 Dec 6.
A high-fat diet (HFD) leads to long-term exposure to gut microbial metabolite secondary bile acids, such as deoxycholic acid (DCA), in the intestine, which is closely linked to colorectal cancer (CRC). Evidence reveals that vasculogenic mimicry (VM) is a critical event for the malignant transformation of cancer. Therefore, this study investigated the crucial roles of DCA in the regulation of VM and the progression of intestinal carcinogenesis. The effects of an HFD on VM formation and epithelial-mesenchymal transition (EMT) in human CRC tissues were investigated. The fecal DCA level was detected in HFD-treated Apc mice. Then the effects of DCA on VM formation, EMT, and vascular endothelial growth factor receptor 2 (VEGFR2) signaling were evaluated in vitro and in vivo. Here we demonstrated that compared with a normal diet, an HFD exacerbated VM formation and EMT in CRC patients. An HFD could alter the composition of the gut microbiota and significantly increase the fecal DCA level in Apc mice. More importantly, DCA promoted tumor cell proliferation, induced EMT, increased VM formation, and activated VEGFR2, which led to intestinal carcinogenesis. In addition, DCA enhanced the proliferation and migration of HCT-116 cells, and induced EMT process and vitro tube formation. Furthermore, the silence of VEGFR2 reduced DCA-induced EMT, VM formation, and migration. Collectively, our results indicated that microbial metabolite DCA promoted VM formation and EMT through VEGFR2 activation, which further exacerbated intestinal carcinogenesis.
高脂肪饮食（HFD）会导致肠道微生物代谢物次级胆酸（如脱氧胆酸（DCA））在肠道中的长期暴露，这与结直肠癌（CRC）密切相关。有证据表明，血管生成拟态（VM）是癌症恶性转化的关键事件。因此，本研究探讨了 DCA 在调节 VM 和肠道癌变进展中的关键作用。研究了 HFD 对人 CRC 组织中 VM 形成和上皮间质转化（EMT）的影响。检测了 HFD 处理的 Apc 小鼠中的粪便 DCA 水平。然后在体外和体内评估了 DCA 对 VM 形成、EMT 和血管内皮生长因子受体 2（VEGFR2）信号的影响。在这里，我们证明与正常饮食相比，HFD 加剧了 CRC 患者的 VM 形成和 EMT。HFD 可以改变肠道微生物群的组成，并显著增加 Apc 小鼠粪便中的 DCA 水平。更重要的是，DCA 促进肿瘤细胞增殖，诱导 EMT，增加 VM 形成，并激活 VEGFR2，从而导致肠道癌变。此外，DCA 增强了 HCT-116 细胞的增殖和迁移，并诱导 EMT 过程和体外管形成。此外，沉默 VEGFR2 减少了 DCA 诱导的 EMT、VM 形成和迁移。总之，我们的结果表明，微生物代谢物 DCA 通过 VEGFR2 激活促进了 VM 形成和 EMT，从而进一步加剧了肠道癌变。
