Mai Zongjiong, Li Yanyu, Zhang Lei, Zhang Hongyu
The Fifth Affiliated Hospital of Sun Yat-sen University Zhuhai, Guangdong, China.
Am J Cancer Res. 2024 Jun 15;14(6):2790-2804. doi: 10.62347/LWRS3363. eCollection 2024.
Metastasis is a principal factor in the poor prognosis of colorectal cancer. Recent studies have found microbial metabolites regulate colorectal cancer metastasis. By analyzing metabolomics data, we identified an essential fecal metabolite citraconate that potentially promotes colorectal cancer metastasis. Next, we tried to reveal its effect on colorectal cancer and the underlying mechanism. Firstly, the response of colorectal cancer cells (HCT116 and MC38 cells) to citraconate was assessed by Cell Counting Kit-8 assay, clonogenic assay, transwell migration and invasion assay. Moreover, we utilized an intra-splenic injection model to evaluate the effect of citraconate on colorectal cancer liver metastasis . Then molecular approaches were employed, including RNA sequencing, mass spectrometry-based metabolomics, western blot, quantitative real-time PCR, cell ferrous iron colorimetric assay and intracellular malondialdehyde measurement. , citraconate promotes the growth of colorectal cancer cells. , citraconate aggravated liver metastasis of colorectal cancer. Mechanistically, downstream genes of NRF2, , and high expression induced by citraconate resulted in resistance to ferroptosis of colorectal cancer cells. In summary, citraconate promotes the malignant progression of colorectal cancer through NRF2-mediated ferroptosis resistance in colorectal cancer cells. Furthermore, our study indicates that fecal metabolite may be crucial in colorectal cancer development.
转移是结直肠癌预后不良的主要因素。最近的研究发现微生物代谢产物可调节结直肠癌转移。通过分析代谢组学数据，我们鉴定出一种重要的粪便代谢产物柠康酸，它可能促进结直肠癌转移。接下来，我们试图揭示其对结直肠癌的影响及潜在机制。首先，通过细胞计数试剂盒-8 检测、克隆形成检测、Transwell 迁移和侵袭检测评估结直肠癌细胞（HCT116 和 MC38 细胞）对柠康酸的反应。此外，我们利用脾内注射模型评估柠康酸对结直肠癌肝转移的影响。然后采用分子方法，包括 RNA 测序、基于质谱的代谢组学、蛋白质免疫印迹、定量实时 PCR、细胞亚铁离子比色测定和细胞内丙二醛测量。柠康酸促进结直肠癌细胞生长。柠康酸加剧了结直肠癌的肝转移。机制上，柠康酸诱导的 NRF2 下游基因及高表达导致结直肠癌细胞对铁死亡产生抗性。总之，柠康酸通过 NRF2 介导的结直肠癌细胞铁死亡抗性促进结直肠癌的恶性进展。此外，我们的研究表明粪便代谢产物可能在结直肠癌发展中起关键作用。
