Berberine may rescue Fusobacterium nucleatum-induced colorectal tumorigenesis by modulating the tumor microenvironment.
Berberine may rescue Fusobacterium nucleatum-induced colorectal tumorigenesis by modulating the tumor microenvironment.
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DOI：
10.18632/oncotarget.5166
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发表时间：
2015-10-13
期刊：
影响因子：
--
通讯作者：
Fang JY
中科院分区：
文献类型：
--
作者：
Yu YN;Yu TC;Zhao HJ;Sun TT;Chen HM;Chen HY;An HF;Weng YR;Yu J;Li M;Qin WX;Ma X;Shen N;Hong J;Fang JY
越来越多的证据表明，结直肠癌(CRC)与肠道微生物区系有关。然而，肠道微生物区系的紊乱和核梭杆菌在结直肠腺瘤-癌序列中的作用尚未得到评估。用454FLX焦磷酸测序仪评价结直肠癌腺瘤-癌序列通路过程中肠道微生物区系的紊乱情况。分别用焦磷酸测序法和Bio-Plex Pro™细胞因子测序法检测了1，2-二甲基肼、核藻和黄连素对小鼠肠道微生物区系和粘膜肿瘤免疫细胞因子的影响。Western blotting检测蛋白质表达。条件致病菌的水平，如梭杆菌、链球菌和肠球菌。在人类粪便和粘膜样本的结直肠腺瘤-癌序列中逐渐增加。核藻处理显著改变了管腔微生物结构，增加了细菌和蠕形微生物(机会致病菌)(P<；0.05=野生型C57BL/6和DMH处理的小鼠)。BBR干预逆转了核盘藻诱导的条件致病菌的增加，与单独饲喂核盘藻的小鼠相比，小鼠IL-21/22/31、CD40L的分泌以及p-STAT3、p-STAT5和p-ERK1/2的表达都发生了逆转。核菌在肠道的定植可能促进结直肠肿瘤的发生。BBR可通过调节肿瘤微环境，阻断肿瘤发生相关通路的激活，挽救核藻诱导的大肠肿瘤发生。
Accumulating evidence links colorectal cancer (CRC) with the intestinal microbiota. However, the disturbance of intestinal microbiota and the role of Fusobacterium nucleatum during the colorectal adenoma-carcinoma sequence have not yet been evaluated. 454 FLX pyrosequencing was used to evaluate the disturbance of intestinal microbiota during the adenoma-carcinoma sequence pathway of CRC. Intestinal microbiota and mucosa tumor-immune cytokines were detected in mice after introducing 1,2-dimethylhydrazine (DMH), F. nucleatum or Berberine (BBR), using pyrosequencing and Bio-Plex Pro™ cytokine assays, respectively. Protein expressions were detected by western blotting. The levels of opportunistic pathogens, such as Fusobacterium, Streptococcus and Enterococcus spp. gradually increased during the colorectal adenoma-carcinoma sequence in human fecal and mucosal samples. F. nucleatum treatment significantly altered lumen microbial structures, with increased Tenericutes and Verrucomicrobia (opportunistic pathogens) (P < 0.05 = in wild-type C57BL/6 and mice with DMH treatment). BBR intervention reversed the F. nucleatum-mediated increase in opportunistic pathogens, and the secretion of IL-21/22/31, CD40L and the expression of p-STAT3, p-STAT5 and p-ERK1/2 in mice, compared with mice fed with F. nucleatum alone. F. nucleatum colonization in the intestine may prompt colorectal tumorigenesis. BBR could rescue F. nucleatum-induced colorectal tumorigenesis by modulating the tumor microenvironment and blocking the activation of tumorigenesis-related pathways.