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

IF 4.3 3区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Gut Pathogens Pub Date : 2024-09-27 DOI:10.1186/s13099-024-00640-w

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

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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.

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阐明核酸镰刀菌分泌的诱变剂在大肠癌致癌过程中的基因毒性

背景：Fusobacterium nucleatum（F. nucleatum）是结直肠癌（CRC）的主要致癌细菌之一，但F. nucleatum如何参与结直肠癌的发生仍是未知数：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，以评估患者生存期与 F. nucleatum 丰度之间的关系。我们发现，在盲肠和升结肠肿瘤患者中，F. nucleatum转录组丰度与突变负荷呈正相关。我们进一步证实，肿瘤中核不动杆菌丰度高和突变负荷高的患者生存率和DNA损伤率都较低。我们还进一步确定，在体外和体内研究中，F. nucleatum条件培养基（Fn. CM）都会诱导DNA损伤。此外，我们还发现了两种F.nucleatum分泌的诱变剂，即DL-高胱氨酸和尿囊酸，可导致DNA损伤：结论：我们的发现阐明了F.nucleatum分泌的突变物的基因毒性，为进一步研究F.nucleatum在CRC致病性中的作用提供了基础。

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来源期刊

Gut Pathogens GASTROENTEROLOGY & HEPATOLOGY-MICROBIOLOGY

CiteScore

7.70

自引率

2.40%

发文量

期刊介绍： Gut Pathogens is a fast publishing, inclusive and prominent international journal which recognizes the need for a publishing platform uniquely tailored to reflect the full breadth of research in the biology and medicine of pathogens, commensals and functional microbiota of the gut. The journal publishes basic, clinical and cutting-edge research on all aspects of the above mentioned organisms including probiotic bacteria and yeasts and their products. The scope also covers the related ecology, molecular genetics, physiology and epidemiology of these microbes. The journal actively invites timely reports on the novel aspects of genomics, metagenomics, microbiota profiling and systems biology. Gut Pathogens will also consider, at the discretion of the editors, descriptive studies identifying a new genome sequence of a gut microbe or a series of related microbes (such as those obtained from new hosts, niches, settings, outbreaks and epidemics) and those obtained from single or multiple hosts at one or different time points (chronological evolution).