期刊
CELLS
卷 9, 期 9, 页码 -出版社
MDPI
DOI: 10.3390/cells9091980
关键词
Fusobacterium nucleatum; inflammation; enteroid; enteroid-derived monolayer; DNA damage; base-excision repair; colorectal cancer; NEIL2; genomic instability; cancer development
类别
资金
- National Institute of Health [DK107585, R01 NS073976, R01HL145477, W81XWH-18-1-0743, R01 AI141630, R01-GM138385, UG3TR002968]
- National Institutes of Health (NIH) [R01 GM124494]
- Edward Mallinckrodt, Jr. Foundation
Colorectal cancer (CRC) is the third most prevalent cancer, while the majority (80-85%) of CRCs are sporadic and are microsatellite stable (MSS), and approximately 15-20% of them display microsatellite instability (MSI). Infection and chronic inflammation are known to induce DNA damage in host tissues and can lead to oncogenic transformation of cells, but the role of DNA repair proteins in microbe-associated CRCs remains unknown. Using CRC-associated microbes such asFusobacterium nucleatum(Fn) in a coculture with murine and human enteroid-derived monolayers (EDMs), here, we show that, among all the key DNA repair proteins, NEIL2, an oxidized base-specific DNA glycosylase, is significantly downregulated afterFninfection.Fninfection of NEIL2-null mouse-derived EDMs showed a significantly higher level of DNA damage, including double-strand breaks and inflammatory cytokines. Several CRC-associated microbes, but not the commensal bacteria, induced the accumulation of DNA damage in EDMs derived from a murine CRC model, andFnhad the most pronounced effect. An analysis of publicly available transcriptomic datasets showed that the downregulation of NEIL2 is often encountered in MSS compared to MSI CRCs. We conclude that the CRC-associated microbeFninduced the downregulation of NEIL2 and consequent accumulation of DNA damage and played critical roles in the progression of CRCs.
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