Oncotarget

Research Papers:

Commensal-infected macrophages induce dedifferentiation and reprogramming of epithelial cells during colorectal carcinogenesis

Xingmin Wang _, Yonghong Yang and Mark M. Huycke

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Oncotarget. 2017; 8:102176-102190. https://doi.org/10.18632/oncotarget.22250

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Abstract

Xingmin Wang1,2, Yonghong Yang3,4 and Mark M. Huycke2,5

1Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA

2The Muchmore Laboratories for Infectious Diseases Research, Oklahoma City VA Health Care System, Oklahoma City, OK 73104, USA

3Gansu Province Children’s Hospital, Lanzhou, Gansu 730030, China

4Key Laboratory of Gastrointestinal Cancer, Lanzhou University Second Hospital, Lanzhou, Gansu 730030, China

5Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73126, USA

Correspondence to:

Xingmin Wang, email: xingmin-wang@ouhsc.edu

Mark M. Huycke, email: mark-huycke@ouhsc.edu

Keywords: macrophage; bystander effect; Wnt/β-catenin; dedifferentiation; cancer stem cell

Received: May 03, 2017    Accepted: September 29, 2017    Published: November 01, 2017

ABSTRACT

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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