Elucidating the genotoxicity of Fusobacterium nucleatum-secreted mutagens in colorectal cancer carcinogenesis
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
Affiliations
Wenye Xu
Microbiota I-Center (MagIC)
Yuchen Zhang
Obstetrics Department, The Third Affiliated Hospital of Zhengzhou University
Dongjiao Chen
Department of Anesthesia and Intensive Care and Peter Hung Pain Research Institute, Faculty of Medicine, The Chinese University of Hong Kong
Dan Huang
Department of Anesthesia and Intensive Care and Peter Hung Pain Research Institute, Faculty of Medicine, The Chinese University of Hong Kong
Yang Zhao
Department of Pharmacology, Shenzhen People’s Hospital, (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology)
Wei Hu
Department of Gastroenterology, Shenzhen Hospital, Southern Medical University
Ling Lin
Microbiota I-Center (MagIC)
Yingzhi Liu
Microbiota I-Center (MagIC)
Shilan Wang
Microbiota I-Center (MagIC)
Judeng Zeng
Department of Anesthesia and Intensive Care and Peter Hung Pain Research Institute, Faculty of Medicine, The Chinese University of Hong Kong
Chuan Xie
Department of Anesthesia and Intensive Care and Peter Hung Pain Research Institute, Faculty of Medicine, The Chinese University of Hong Kong
Hung Chan
Department of Anesthesia and Intensive Care and Peter Hung Pain Research Institute, Faculty of Medicine, The Chinese University of Hong Kong
Qing Li
Department of Anesthesia and Intensive Care and Peter Hung Pain Research Institute, Faculty of Medicine, The Chinese University of Hong Kong
Huarong Chen
Department of Anesthesia and Intensive Care and Peter Hung Pain Research Institute, Faculty of Medicine, The Chinese University of Hong Kong
Xiaodong Liu
Department of Anesthesia and Intensive Care and Peter Hung Pain Research Institute, Faculty of Medicine, The Chinese University of Hong Kong
Sunny H. Wong
Lee Kong Chian School of Medicine, Nanyang Technological University
Jun Yu
Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong
Francis K. L. Chan
Microbiota I-Center (MagIC)
Matthew T. V. Chan
Department of Anesthesia and Intensive Care and Peter Hung Pain Research Institute, Faculty of Medicine, The Chinese University of Hong Kong
Siew C. Ng
Microbiota I-Center (MagIC)
William K. K. Wu
Department of Anesthesia and Intensive Care and Peter Hung Pain Research Institute, Faculty of Medicine, The Chinese University of Hong Kong
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.
