IRF3 prevents colorectal tumorigenesis via inhibiting the nuclear translocation of β-catenin

Miao Tian, Xiumei Wang, Jihong Sun, Wenlong Lin, Lumin Chen, Shengduo Liu, Ximei Wu, Liyun Shi, Pinglong Xu, Xiujun Cai () and Xiaojian Wang ()
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Miao Tian: Zhejiang University
Xiumei Wang: Zhejiang University
Jihong Sun: Zhejiang University
Wenlong Lin: Zhejiang University
Lumin Chen: Zhejiang University
Shengduo Liu: Zhejiang University
Ximei Wu: Zhejiang University
Liyun Shi: Nanjing University of Chinese Medicine
Pinglong Xu: Zhejiang University
Xiujun Cai: Zhejiang University School of Medicine
Xiaojian Wang: Zhejiang University

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract Occurrence of Colorectal cancer (CRC) is relevant with gut microbiota. However, role of IRF3, a key signaling mediator in innate immune sensing, has been barely investigated in CRC. Here, we unexpectedly found that the IRF3 deficient mice are hyper-susceptible to the development of intestinal tumor in AOM/DSS and Apcmin/+ models. Genetic ablation of IRF3 profoundly promotes the proliferation of intestinal epithelial cells via aberrantly activating Wnt signaling. Mechanically, IRF3 in resting state robustly associates with the active β-catenin in the cytoplasm, thus preventing its nuclear translocation and cell proliferation, which can be relieved upon microbe-induced activation of IRF3. In accordance, the survival of CRC is clinically correlated with the expression level of IRF3. Therefore, our study identifies IRF3 as a negative regulator of the Wnt/β-catenin pathway and a potential prognosis marker for Wnt-related tumorigenesis, and describes an intriguing link between gut microbiota and CRC via the IRF3-β-catenin axis.

Date: 2020
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DOI: 10.1038/s41467-020-19627-7

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