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

doi:10.1186/s13099-024-00640-w

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

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

Authors

Wenye Xu^#^{1

2}, Yuchen Zhang^#³, Dongjiao Chen^#², Dan Huang^#², Yang Zhao⁴, Wei Hu⁵, Ling Lin^{1

2}, Yingzhi Liu^{1

2}, Shilan Wang^{1

6}, Judeng Zeng^{2

7}, Chuan Xie^{2

8}, Hung Chan², Qing Li^{2

9

7}, Huarong Chen^{2

9

7}, Xiaodong Liu^{2

7}, Sunny H Wong¹⁰, Jun Yu^{6

9

7}, Francis K L Chan^{1

11}, Matthew T V Chan¹², Siew C Ng^{13

14

15}, William K K Wu^{16

17

18}, Lin Zhang^{19

20

21}

Affiliations

¹ Microbiota I-Center (MagIC), Hong Kong, SAR, China.
² 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.
³ Obstetrics Department, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁴ Department of Pharmacology, Shenzhen People's Hospital, (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, China.
⁵ Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangdong, China.
⁶ Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China.
⁷ CUHK Shenzhen Research Institute, Shenzhen, 518172, China.
⁸ Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China.
⁹ State Key Laboratory of Digestive Diseases, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, SAR, China.
¹⁰ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, 639798, Singapore.
¹¹ Centre for Gut Microbiota Research, The Chinese University of Hong Kong, Hong Kong, SAR, China.
¹² 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. mtvchan@cuhk.edu.hk.
¹³ Microbiota I-Center (MagIC), Hong Kong, SAR, China. siewchienng@cuhk.edu.hk.
¹⁴ Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China. siewchienng@cuhk.edu.hk.
¹⁵ State Key Laboratory of Digestive Diseases, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, SAR, China. siewchienng@cuhk.edu.hk.
¹⁶ 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. wukakei@cuhk.edu.hk.
¹⁷ State Key Laboratory of Digestive Diseases, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, SAR, China. wukakei@cuhk.edu.hk.
¹⁸ CUHK Shenzhen Research Institute, Shenzhen, 518172, China. wukakei@cuhk.edu.hk.
¹⁹ Microbiota I-Center (MagIC), Hong Kong, SAR, China. linzhang@cuhk.edu.hk.
²⁰ 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. linzhang@cuhk.edu.hk.
²¹ State Key Laboratory of Digestive Diseases, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, SAR, China. linzhang@cuhk.edu.hk.

^# Contributed equally.

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.

Keywords: F. nucleatum; Allantoic acid; CRC; DL-homocystine; DNA damage.

Grants and funding

4054683/Direct Grant in Chinese University of Hong Kong