阐明具核梭杆菌分泌的诱变剂在结直肠癌发生中的遗传毒性。

Elucidating the genotoxicity of Fusobacterium nucleatum-secreted mutagens in colorectal cancer carcinogenesis.

作者信息

Xu Wenye, Zhang Yuchen, Chen Dongjiao, Huang Dan, Zhao Yang, Hu Wei, Lin Ling, Liu Yingzhi, Wang Shilan, Zeng Judeng, Xie Chuan, Chan Hung, Li Qing, Chen Huarong, Liu Xiaodong, Wong Sunny H, Yu Jun, Chan Francis K L, Chan Matthew T V, Ng Siew C, Wu William K K, Zhang Lin

机构信息

Microbiota I-Center (MagIC), Hong Kong, SAR, China.

Department of Anesthesia and Intensive Care and Peter Hung Pain Research Institute, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China.

出版信息

Gut Pathog. 2024 Sep 27;16(1):50. doi: 10.1186/s13099-024-00640-w.

DOI:10.1186/s13099-024-00640-w

PMID:39334474

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11438217/

Abstract

BACKGROUND

Fusobacterium nucleatum (F. nucleatum) is one of the key tumorigenic bacteria in colorectal cancer (CRC), yet how F. nucleatum is involved in colorectal cancer carcinogenesis remains unknown.

RESULTS

In the present study, we carried out PathSeq analysis on RNA sequencing data from the 430 primary colon adenocarcinomas in TCGA database to assess the relationship between patients' survival and F. nucleatum abundance. Among patients with cecum and ascending colon tumors, we found that F. nucleatum transcriptome abundance is positively correlated with mutation load. We further demonstrated that patients with both high tumoral abundance of F. nucleatum and high mutation load exhibited poorer survival and DNA damage. We furthermore determined that F. nucleatum-conditioned medium (Fn. CM) induces DNA damage in both in vitro and in vivo studies. In addition, two F. nucleatum-secreted mutagens, namely DL-homocystine and allantoic acid, were identified to lead to DNA damage.

CONCLUSIONS

Our finding delineates the genotoxicity of F.nucleatum-secreted mutagens, which provides a basis for further work to investigate the role of F. nucleatum in the pathogenicity of CRC.

摘要

背景

具核梭杆菌（F. nucleatum）是结直肠癌（CRC）中关键的致瘤细菌之一，但具核梭杆菌如何参与结直肠癌的致癌过程仍不清楚。

结果

在本研究中，我们对TCGA数据库中430例原发性结肠腺癌的RNA测序数据进行了PathSeq分析，以评估患者生存与具核梭杆菌丰度之间的关系。在患有盲肠和升结肠肿瘤的患者中，我们发现具核梭杆菌转录组丰度与突变负荷呈正相关。我们进一步证明，具核梭杆菌肿瘤丰度高且突变负荷高的患者生存较差且存在DNA损伤。我们还确定，具核梭杆菌条件培养基（Fn. CM）在体外和体内研究中均诱导DNA损伤。此外，鉴定出两种具核梭杆菌分泌的诱变剂，即DL-高胱氨酸和尿囊酸，可导致DNA损伤。