MyD88 in myofibroblasts enhances colitis-associated tumorigenesis via promoting macrophage M2 polarization

Qi Yuan; Jianchun Gu; Jie Zhang; Shi Liu; Qinchuan Wang; Tian Tian; Zhinan Chen; Jinhua Zhang

doi:10.1016/j.celrep.2021.108724

MyD88 in myofibroblasts enhances colitis-associated tumorigenesis via promoting macrophage M2 polarization

Cell Rep. 2021 Feb 2;34(5):108724. doi: 10.1016/j.celrep.2021.108724.

Authors

Qi Yuan¹, Jianchun Gu², Jie Zhang¹, Shi Liu¹, Qinchuan Wang³, Tian Tian¹, Zhinan Chen⁴, Jinhua Zhang⁵

Affiliations

¹ The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing, P.R. China.
² Department of Oncology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
³ Department of Surgical Oncology, Affiliated Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
⁴ The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing, P.R. China; Cell Engineering Research Center and Department of Cell Biology, State Key Laboratory of Cancer, Fourth Military Medical University, Xi'an, P.R. China.
⁵ The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing, P.R. China. Electronic address: zhangjh@bjtu.edu.cn.

PMID: 33535045
DOI: 10.1016/j.celrep.2021.108724

Abstract

The signal adaptor MyD88, an essential component of TLR signaling, plays an important role in gut-microbiome interactions. However, its contribution to colitis-associated cancer (CAC) is still controversial. Far less is known about the specific effects of MyD88 signaling in myofibroblasts in CAC development. Here, we used a CAC mouse model in which MyD88 was selectively depleted in myofibroblasts. Myofibroblast MyD88-deficient mice are resistant to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced tumorigenesis, as evidenced by the decrease in the number and sizes of tumors. MyD88 deficiency in myofibroblasts attenuates intestinal epithelial cell (IEC) proliferation after acute DSS-induced colitis. Furthermore, MyD88 signaling in myofibroblasts increases the secretion of osteopontin (OPN), which promotes macrophage M2 polarization through binding to α_vβ₃ and CD44, leading to activation of the STAT3/PPARγ pathway. Thus, MyD88 signaling in myofibroblasts crucially contributes to colorectal cancer development and provides a promising therapeutic target for the prevention of colitis-associated carcinogenesis.

Keywords: MyD88; colitis-associated cancer; macrophage polarization.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinogenesis
Cell Polarity / physiology
Disease Models, Animal
Humans
Macrophages / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Myeloid Differentiation Factor 88 / metabolism*
Myofibroblasts / cytology
Myofibroblasts / metabolism*
RAW 264.7 Cells

Substances

MYD88 protein, human
Myd88 protein, mouse
Myeloid Differentiation Factor 88