Commensal-infected macrophages induce dedifferentiation and reprogramming of epithelial cells during colorectal carcinogenesis.
Commensal-infected macrophages induce dedifferentiation and reprogramming of epithelial cells during colorectal carcinogenesis.
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DOI：
10.18632/oncotarget.22250
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发表时间：
2017-11-24
期刊：
影响因子：
--
通讯作者：
Huycke MM
中科院分区：
文献类型：
--
作者：
Wang X;Yang Y;Huycke MM
结肠微生物组通过尚不清楚的机制促进结直肠癌的发生。我们已经证明，共生极化巨噬细胞通过微生物诱导的旁观者效应（MIBE）诱导基因突变、染色体不稳定和内源性转化。在这项研究中，我们发现 MIBE 激活与结直肠癌干细胞 (CSC) 去分化、重编程和发育相关的 Wnt/β-连环蛋白信号传导和多能转录因子。将小鼠原代结肠上皮细胞 (YAMC) 暴露于粪肠球菌感染的巨噬细胞会增加 Wnt3α 表达，同时抑制 Wnt 抑制因子 1 (Wif1)。通过增加活性 β-catenin 和 Tcf4 证实了 Wnt/β-catenin 的激活。在体内，与假定植小鼠相比，粪肠球菌定植的 Il10 敲除小鼠的结肠活检中存在明显的活性 β-连环蛋白。这种作用部分是由 4-羟基-2-壬烯醛和肿瘤坏死因子 α 介导的。 MIBE 还激活了粪肠球菌定植的 Il10 敲除小鼠的 YAMC 细胞和结肠中的多能转录因子 c-Myc、Klf4、Oct4 和 Sox2。这些转录因子与细胞重编程、去分化和结直肠 CSC 祖细胞的诱导有关。暴露于 MIBE 的 YAMC 细胞中 Dclk1 和 CD44（两种结直肠 CSC 标记物）的表达增加支持了这一点。最后，与正常结肠活检和增生性息肉相比，人管状腺瘤和侵袭性结直肠癌中 DCLK1 表达增加。使用 FH535 和 CTNNB1 特异性小干扰 RNA 阻断 β-catenin/TCF4 信号传导可降低 HCT116 人结肠癌细胞中 DCLK1 的表达。这些发现提供了微生物诱导结直肠癌的机制，并确定了预防结直肠癌的新的潜在靶标。
The colonic microbiome contributes to the initiation of colorectal cancer through poorly characterized mechanisms. We have shown that commensal-polarized macrophages induce gene mutation, chromosomal instability, and endogenous transformation through microbiome-induced bystander effects (MIBE). In this study we show that MIBE activates Wnt/β-catenin signaling and pluripotent transcription factors associated with dedifferentiation, reprogramming, and the development of colorectal cancer stem cells (CSCs). Exposure of murine primary colon epithelial cells (YAMC) to Enterococcus faecalis-infected macrophages increased Wnt3α expression while suppressing Wnt inhibitor factor 1 (Wif1). Wnt/β-catenin activation was confirmed by increased active β-catenin and Tcf4. in vivo, active β-catenin was evident in colon biopsies from E. faecalis-colonized Il10 knockout mice compared to sham-colonized mice. This effect was mediated, in part, by 4-hydroxy-2-nonenal and tumor necrosis factor α. MIBE also activated pluripotent transcription factors c-Myc, Klf4, Oct4, and Sox2 in YAMC cells and colons from E. faecalis-colonized Il10 knockout mice. These transcription factors are associated with cellular reprogramming, dedifferentiation, and induction of colorectal CSC progenitors. In support of this was an increase in the expression of Dclk1 and CD44, two colorectal CSC markers, in YAMC cells that were exposed to MIBE. Finally, compared to normal colon biopsies and hyperplastic polyps, DCLK1 expression increased in human tubular adenomas and invasive colorectal cancers. Blocking β-catenin/TCF4 signaling using FH535 and CTNNB1-specific small interfering RNA decreased DCLK1 expression in HCT116 human colon cancer cells. These findings provide mechanism for microbiome-induced colorectal cancer and identify new potential targets for colorectal cancer prevention.
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影响因子：
3.7
作者：
Cosín-Roger J;Ortiz-Masiá D;Calatayud S;Hernández C;Alvarez A;Hinojosa J;Esplugues JV;Barrachina MD
通讯作者：
Barrachina MD
影响因子：
--
作者：
Chandrakesan P;Weygant N;May R;Qu D;Chinthalapally HR;Sureban SM;Ali N;Lightfoot SA;Umar S;Houchen CW
通讯作者：
Houchen CW
影响因子：
10.5
作者：
Cole, Megan F.;Johnstone, Sarah E.;Young, Richard A.
通讯作者：
Young, Richard A.
影响因子：
30.3
作者：
Rubinstein MR;Wang X;Liu W;Hao Y;Cai G;Han YW
通讯作者：
Han YW
影响因子：
56.9
作者：
He, TC;Sparks, AB;Kinzler, KW
通讯作者：
Kinzler, KW