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Enterotoxigenic Bacteroides fragilis Promotes Intestinal Inflammation and Malignancy by Inhibiting Exosome-Packaged miR-149-3p
Abstract
BACKGROUD & AIMS Enterotoxigenic Bacteroides fragilis (ETBF) is strongly associated with the occurrence of inflammatory bowel disease(IBD), colitis-associated colorectal cancer (CAC) and colorectal cancer (CRC). However, the mechanism of ETBF-induced intestinal inflammation and tumorigenesis remains unclear. METHODS microRNA sequencing was utilized to detect the differentially expressed miRNAs both in ETBF-treated cells and exosomes derived from ETBF-inoculated cells. Cell Counting Kit-8 assays were used to evaluate the effect of ETBF and exosomes on CRC cell proliferation. The biological role and mechanism of ETBF-mediated miR-149-3p in colitis and colon carcinogenesis were determined both in vitro and in vivo. RESULTS ETBF promoted CRC cell proliferation by down-regulating miR-149-3p both in vitro and in vivo. ETBF-downregulated miR-149-3p depended on METTL14-mediated m6A methylation. As the target gene of miR-149-3p, PHF5A transactivated SOD2 through regulating KAT2A mRNA alternative splicing after ETBF treatment in CRC cells. miR-149-3p could be released in exosomes and mediated intercellular communication by modulating Th17 differentiation. The level of plasma exosomal miR-149-3p was gradually decreased from healthy control to IBD and CRC patients. MiR-149-3p, existing in plasma exosomes, negatively correlated with the abundance of ETBF in IBD and CRC patients. CONCLUSIONS Exosomal miR-149-3p derived from ETBF-treated cells facilitated Th17 cell differentiation. ETBF-induced colorectal carcinogenesis depended on downregulating miR-149-3p and further promoting PHF5A-mediated RNA alternative splicing of KAT2A in CRC cells. targeting the ETBF/miR-149-3p pathway presents a promising approach to treat intestinal inflammatory and colorectal cancer patients with high amount of ETBF.
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Metadata
- Authors
- Cao, Y., Wang, Z., Yan, Y., Ji, L., He, J., Xuan, B., Shen, C., Ma, Y., Jiang, S., Ma, D., Tong, T., Zhang, X., Gao, Z., Zhu, X., Fang, J.-Y., Chen, H., & Hong, J.
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2021-11
- Volume
- 161
- Issue
- 5
- Pages
- 1552-1566.e12
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W3187291031
- Cited by
- 298
- References
- 52
- FWCI
- 15.51
- Type
- journal article
- Language
- en
- Open access
- closed
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- Cao, Y., Wang, Z., Yan, Y., Ji, L., He, J., Xuan, B., Shen, C., Ma, Y., Jiang, S., Ma, D., Tong, T., Zhang, X., Gao, Z., Zhu, X., Fang, J.-Y., Chen, H., & Hong, J. (2021). Enterotoxigenic Bacteroides fragilis Promotes Intestinal Inflammation and Malignancy by Inhibiting Exosome-Packaged miR-149-3p. Gastroenterology. https://doi.org/10.1053/j.gastro.2021.08.003
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