Enterotoxigenic Bacteroides fragilis Promotes Intestinal Inflammation and Malignancy by Inhibiting Exosome-Packaged miR-149-3p
Enterotoxigenic Bacteroides fragilis Promotes Intestinal Inflammation and Malignancy by Inhibiting Exosome-Packaged miR-149-3p
复制标题
DOI：
10.1053/j.gastro.2021.08.003
复制
发表时间：
2021-10-21
期刊：
影响因子：
29.4
通讯作者：
Hong, Jie
中科院分区：
文献类型：
--
作者：
Cao, Yingying;Wang, Zhenhua;Hong, Jie
背景与目的：产肠毒素脆弱类杆菌（ETBF）与炎症性肠病（IBD）、结肠炎相关性结直肠癌和结直肠癌（CRC）的发生密切相关。然而，ETBF诱导肠道炎症和肿瘤发生的机制仍不清楚。方法：microRNA测序用于检测ETBF处理的细胞和源自ETBF接种的细胞的外来体中差异表达的microRNA。使用细胞计数试剂盒8测定来评估ETBF和外来体对CRC细胞增殖的影响。在体外和体内确定ETBF介导的miR-149- 3 p在结肠炎和结肠癌发生中的生物学作用和机制。结果：ETBF通过下调miR-149- 3 p促进结直肠癌细胞增殖。ETBF下调miR-149- 3 p依赖于胃L14介导的N6-甲基腺苷甲基化。PHF 5A作为miR-149- 3 p的靶基因，在大肠癌细胞中通过调节ETBF处理后KAT 2A信使RNA的选择性剪接而反式激活SOD 2。miR-149- 3 p可在外泌体中释放，并通过调节T-helper 17型细胞分化介导细胞间通讯。从健康对照个体到IBD和CRC患者，血浆外泌体miR-149- 3 p的水平逐渐降低。存在于血浆exosomes中的miR-149- 3 p与IBD和CRC患者中ETBF的丰度呈负相关。结论：ETBF处理的细胞来源的外泌体miR-149- 3 p促进Thelper type 17细胞的分化。ETBF诱导的结直肠癌发生依赖于下调miR-149- 3 p并进一步促进PHF 5A介导的CRC细胞中KAT 2A的RNA选择性剪接。靶向ETBF/miR-149- 3 p通路提供了一种治疗具有高ETBF量的肠道炎症和CRC患者的有希望的方法。
BACKGROUND & AIMS: Enterotoxigenic Bacteroides fragilis (ETBF) is strongly associated with the occurrence of inflammatory bowel disease (IBD), colitis-associated colorectal cancer, and colorectal cancer (CRC). However, the mechanism of ETBF-induced intestinal inflammation and tumorigenesis remains unclear. METHODS: microRNA sequencing was used to detect the differentially expressed microRNAs in both 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-down-regulated miR-149-3p depended on METTL14-mediated N6-methyladenosine methylation. As the target gene of miR-149-3p, PHF5A transactivated SOD2 through regulating KAT2A messenger RNA alternative splicing after ETBF treatment in CRC cells. miR-149-3p could be released in exosomes and mediated intercellular communication by modulating T-helper type 17 cell differentiation. The level of plasma exosomal miR-149-3p was gradually decreased from healthy control individuals to patients with IBD and CRC. miR-149-3p, existing in plasma exosomes, negatively correlated with the abundance of ETBF in patients with IBD and CRC. CONCLUSIONS: Exosomal miR-149-3p derived from ETBF-treated cells facilitated Thelper type 17 cell differentiation. ETBF-induced colorectal carcinogenesis depended on down-regulating 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 patients with intestinal inflammation and CRC with a high amount of ETBF.