综合血浆和粪便代谢组学可识别腺瘤-结直肠癌进展中的功能代谢物并作为早期诊断生物标志物。
Integrative plasma and fecal metabolomics identify functional metabolites in adenoma-colorectal cancer progression and as early diagnostic biomarkers.
发表日期：2024 Aug 12
作者：
Yang Sun, Xiang Zhang, Dong Hang, Harry Cheuk-Hay Lau, Jie Du, Chuanfa Liu, Mingxu Xie, Yasi Pan, Le Wang, Cong Liang, Xingyu Zhou, Danyu Chen, Jiamei Rong, Zengren Zhao, Alvin Ho-Kwan Cheung, Yuet Wu, Hongyan Gou, Chi Chun Wong, Lingbin Du, Junliang Deng, Zhibin Hu, Hongbing Shen, Yinglei Miao, Jun Yu
来源：
CANCER CELL
摘要：
结直肠癌 (CRC) 进展（正常腺瘤-CRC）中血浆和粪便代谢组的变化仍不清楚。在这里，血浆和粪便样本是从四个独立队列的 1,251 名个体中收集的（422 名 CRC、399 名结直肠腺瘤 [CRA] 和 430 名正常对照 [NC]）。通过代谢组学分析，鉴定出在 NC、CRA 和 CRC 之间具有一致变化的特征血浆和粪便代谢物，包括富含 CRC 的油酸和缺乏 CRC 的别胆酸。油酸在 CRC 细胞、患者来源的类器官和两种小鼠 CRC 模型中表现出促肿瘤作用，而别胆酸则具有相反的作用。通过综合分析，我们发现油酸或别胆酸分别直接与CRC细胞中的α-烯醇化酶或法尼醇X受体1结合，以调节癌症相关通路。在临床上，我们建立了一个由 17 种血浆代谢物组成的小组，可以在一个发现组和三个验证组中准确诊断 CRC（AUC = 0.848-0.987）。总体而言，我们在 CRC 中描述了血浆和粪便代谢组的代谢特征、机制意义和诊断潜力。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。
Changes in plasma and fecal metabolomes in colorectal cancer (CRC) progression (normal-adenoma-CRC) remain unclear. Here, plasma and fecal samples were collected from four independent cohorts of 1,251 individuals (422 CRC, 399 colorectal adenoma [CRA], and 430 normal controls [NC]). By metabolomic profiling, signature plasma and fecal metabolites with consistent shift across NC, CRA, and CRC are identified, including CRC-enriched oleic acid and CRC-depleted allocholic acid. Oleic acid exhibits pro-tumorigenic effects in CRC cells, patient-derived organoids, and two murine CRC models, whereas allocholic acid has opposing effects. By integrative analysis, we found that oleic acid or allocholic acid directly binds to α-enolase or farnesoid X receptor-1 in CRC cells, respectively, to modulate cancer-associated pathways. Clinically, we establish a panel of 17 plasma metabolites that accurately diagnoses CRC in a discovery and three validation cohorts (AUC = 0.848-0.987). Overall, we characterize metabolite signatures, mechanistic significance, and diagnostic potential of plasma and fecal metabolomes in CRC.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.