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

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2024年9月27日

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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

摘要

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.