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. 2015 Oct 13;6(31):32013-26.
doi: 10.18632/oncotarget.5166.

Berberine may rescue Fusobacterium nucleatum-induced colorectal tumorigenesis by modulating the tumor microenvironment

Ya-Nan Yu  1   2 , Ta-Chung Yu  1 , Hui-Jun Zhao  1 , Tian-Tian Sun  1 , Hui-Min Chen  1 , Hao-Yan Chen  1 , Hui-Fang An  3 , Yu-Rong Weng  1 , Jun Yu  4 , Min Li  5 , Wen-Xin Qin  6 , Xiong Ma  1 , Nan Shen  7 , Jie Hong  1 , Jing-Yuan Fang  1
Affiliations

Berberine may rescue Fusobacterium nucleatum-induced colorectal tumorigenesis by modulating the tumor microenvironment

Ya-Nan Yu et al. Oncotarget. .

Abstract

Background: Accumulating evidence links colorectal cancer (CRC) with the intestinal microbiota VSports手机版. However, the disturbance of intestinal microbiota and the role of Fusobacterium nucleatum during the colorectal adenoma-carcinoma sequence have not yet been evaluated. .

Methods: 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 V体育安卓版. nucleatum or Berberine (BBR), using pyrosequencing and Bio-Plex Pro™ cytokine assays, respectively. Protein expressions were detected by western blotting. .

Results: 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 V体育ios版. nucleatum alone. .

Conclusions: F. nucleatum colonization in the intestine may prompt colorectal tumorigenesis. BBR could rescue F VSports最新版本. nucleatum-induced colorectal tumorigenesis by modulating the tumor microenvironment and blocking the activation of tumorigenesis-related pathways. .

Keywords: Fusobacterium nucleatum; berberine; colorectal tumorigenesis; intestinal microbiota; tumor-immune cytokine V体育平台登录. .

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare no potential conflicts of interest.

Figures

Figure 1
Figure 1. Intestinal microbiota structures among the FN group (n = 52), FA group (n = 47) and FC group (n = 42)
A. Principal component analysis (PCA) scores plot based on unweighted UniFrac metrics. Each symbol represents a sample. B. PCA scores plot based on unweighted UniFrac metrics. Each point represents the mean principal component scores of all populations in a different group, and the error bar represents the standard deviation. C. Relative abundance of lumen microbiota distribution in the negative control (FN) group (n = 52) at the phylum level. D. Relative abundance of lumen microbiota distribution in the CRA (FA) group (n = 47) at the phylum level. E. Relative abundance of lumen microbiota distribution in the CRC (FC) group (n = 42) at the phylum level.
Figure 2
Figure 2. Intestine tumorigenesis and lumenal microbiota structures in mice with treated with Fusobacterium nucleatum or BBR
A. Colon ACF in wild-type C57BL/6 mice observed by staining with 0.2% methylene blue under a light microscope at 8 weeks (n = 10 per group). ACF are highlighted with red arrows. B. Intestine tumorigenesis in wild-type C57BL/6 mice at 20 weeks (n = 10 per group). C. Intestine tumorigenesis in C57BL/6-APCMin/+ mice at 8 weeks (n = 10 per group). Two-sided P-values < 0.05 were considered statistically significant. *P < 0.05 **P < 0.01. D. F. nucleatum colonization altered intestinal microbiota structures in mice. E. BBR modulated the microbiota disturbance induced by F. nucleatum. Each point represents the mean principal component scores of all population in the different groups, and the error bar represents the standard deviation.
Figure 3
Figure 3. Lumen microbiota distribution at the phylum level in mice treated with A. bacteria or B. BBR
The relative contribution of a phylum was calculated as the percentage of the sequences of this phylum to all sequences in this population. Mean ± SEM (standard error of mean) was calculated according to percentage of the sequences of this phylum to all sequences in each individual. The differences in relative abundances were calculated using Mann-Whitney U test. Two-sided P-values < 0.05 were considered statistically significant. *P < 0.05, compared with Ctr group; ΔP < 0.05, compared with DMH group; #P < 0.05, compared with Fn+DMH group.
Figure 4
Figure 4. BBR inhibited colon tumorigenesis induced by F. nucleatum in mice by modulating the expression of mucosa tumor-immune cytokines
A. Colon ACF and B. tumors counted in wild-type C57BL/6 mice with BBR intervention at different times. Two-sided P-values < 0.05 were considered statistically significant. **P < 0.01. C. F. nucleatum colonization altered the expression of mucosa tumor-immune cytokines in mice. *P < 0.05 and **P < 0.01, compared with the Ctr group; ▲P < 0.05 and ▲▲P < 0.01, compared with the DMH group. D. BBR modulated the mucosa tumor-immune cytokines secretion induced by F. nucleatum. ▲P < 0.05 and ▲▲P < 0.01, compared with the Fn+DMH group.
Figure 5
Figure 5. BBR inhibited colon tumorigenesis induced by F. nucleatum in mice by modulating JAK/STAT and MAPK pathways
Western blot assays were performed to measure the expressions of STAT3, STAT5, ERK1/2, AKT1/2, p-STAT3, p-STAT5, p-ERK1/2 and p-AKT1/2 with different treatments in wild-type C57BL/6 mice A. and in C57BL/6-APCMin/+ mice B, C. The summarized analysis of the western blot is shown in wild-type C57BL/6 mice with different treatments. *P < 0.05 and **P < 0.01, compared with the Ctr group; ▲P < 0.05 and ▲▲P < 0.01, compared with the Fn+DMH group. D. The summarized analysis of western blot is shown in C57BL/6-APCMin/+ mice with different treatments. *P < 0.05 and **P < 0.01, compared with the Ctr group; ▲P < 0.05 and ▲▲P < 0.01, compared with the Fn group.
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