期刊
CANCER DISCOVERY
卷 12, 期 1, 页码 236-249出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-21-0912
关键词
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类别
资金
- NIH [R01GM111682, R01CA244350, R21AI137719, T32CA009110]
- American Heart Association [19PRE34380234]
- American Association of Immunologists (Career in Immunology Fellowship)
- Germ-Free Facility of Johns Hopkins University
- Bloomberg Philanthropies
- American Cancer Society [RSG-13-05201-MPC]
- Department of Defense [W81XWH-19-1-0479]
- Willowcroft Foundation [1902]
- Graham Memorial Trust
This study identified a novel genotoxin called UshA in attaching/effacing pathogens, which triggers DNA damage and initiates tumorigenic transformation during bacterial infections. Furthermore, it was found that UshA plays a critical role in accelerating colon tumorigenesis in mice. These findings highlight the importance of UshA in the development of colon cancer caused by bacterial infections.
Chronic and low-grade inflammation associated with persistent bacterial infections has been linked to colon tumor development; however, the impact of transient and self-limited infections in bacterially driven colon tumorigenesis has remained enigmatic. Here we report that UshA is a novel genotoxin in attaching/effacing (A/E) pathogens, which include the human pathogens enteropathogenic Escherichia coli, enterohemorrhagic E. coli, and their murine equivalent Citrobacter rodentium (CR). UshA harbors direct DNA digestion activity with a catalytic histidine-aspartic acid dyad. Injected via the type III secretion system (T3SS) into host cells, UshA triggers DNA damage and initiates tumorigenic transformation during infections in vitro and in vivo . Moreover, UshA plays an indispensable role in CR infection-accelerated colon tumorigenesis in genetically susceptible Apc(Min Delta 716/+) mice. Collectively, our results reveal that UshA, functioning as a bacterial T3SS-dependent genotoxin, plays a critical role in prompting transient and noninvasive bacterial infection-accelerated colon tumorigenesis in mice. SIGNIFICANCE: We identified UshA, a novel T3SS-dependent genotoxin in A/E pathogens that possesses direct DNA digestion activity and confers bacterially accelerated colon tumorigenesis in mice. Our results demonstrate that acute and noninvasive infection with A/E pathogens harbors a far-reaching impact on the development of colon cancer.
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