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STAT6 Induces MLCK1-Dependent Epithelial Tight Junction Dysfunction and Promotes Intestinal Inflammation and Tumorigenesis

59 Pages Posted: 17 Jan 2019 Publication Status: Review Complete

See all articles by Yuli Lin

Yuli Lin

Fudan University - Department of Immunology

Bingji Li

Fudan University - Department of Immunology

Xuguang Yang

Shanghai University of Traditional Chinese Medicine - Cancer Institute; Shanghai Jiao Tong University (SJTU) - Department of Oncology

Yusheng Chen

Fudan University - Department of General Surgery

Ting Liu

Fudan University - Department of Immunology

Tiancong Shi

Fudan University - Department of Immunology

Bo Deng

Shanghai Jiao Tong University (SJTU) - Division of Nephrology

Yubin Zhang

Fudan University - School of Public Health; Fudan University - Key Laboratory of Public Health

Lijun Jia

Shanghai Jiao Tong University (SJTU) - Department of Oncology; Shanghai University of Traditional Chinese Medicine - Cancer Institute

Zhengfan Jiang

Peking University - State Key Laboratory of Protein and Plant Gene Research

Rui He

Fudan University - Department of Immunology

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Abstract

Enhanced gut permeability due to dysregulated epithelial tight junction is often associated with inflammatory bowel diseases (IBD), which have greater risk for developing colorectal cancer. We demonstrated that non-hematopoietic STAT6 was able to enhance gut permeability and microbiota translocation to induce excessive colonic inflammation that facilitates tumorigenesis. We identified IL-13 as the upstream activator of epithelial STAT6 to mediate colonic inflammation and type 2 innate lymphoid cells (ILC2) as the major source of IL-13 in a microbiota-dependent way. Mechanistically, long myosin light chain kinase (MLCK1) was identified as a transcriptional target of STAT6, leading to epithelial tight junction dysfunction and microbiota-driven colitis. Moreover, STAT6 inhibitor efficiently inhibited intestinal tumor development. Our study reveals a direct role of STAT6 in the disruption of epithelial tight junction integrity, which could be a causal factor for colonic inflammation, and suggests STAT6 as a potential therapeutic and prophylactic target for IBD and colitis-associated cancer.

Suggested Citation

Lin, Yuli and Li, Bingji and Yang, Xuguang and Chen, Yusheng and Liu, Ting and Shi, Tiancong and Deng, Bo and Zhang, Yubin and Jia, Lijun and Jiang, Zhengfan and He, Rui, STAT6 Induces MLCK1-Dependent Epithelial Tight Junction Dysfunction and Promotes Intestinal Inflammation and Tumorigenesis (Jaanuary 16, 2019). Available at SSRN: https://ssrn.com/abstract=3316798 or http://dx.doi.org/10.2139/ssrn.3316798
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Yuli Lin

Fudan University - Department of Immunology

Shanghai, 200032
Chile

Bingji Li

Fudan University - Department of Immunology

Shanghai, 200032
Chile

Xuguang Yang

Shanghai University of Traditional Chinese Medicine - Cancer Institute

Shanghai, 200032
China

Shanghai Jiao Tong University (SJTU) - Department of Oncology

Shanghai
China

Yusheng Chen

Fudan University - Department of General Surgery

Shanghai, 200032
China

Ting Liu

Fudan University - Department of Immunology

Shanghai, 200032
Chile

Tiancong Shi

Fudan University - Department of Immunology

Shanghai, 200032
Chile

Bo Deng

Shanghai Jiao Tong University (SJTU) - Division of Nephrology

Shanghai, 200011
China

Yubin Zhang

Fudan University - School of Public Health

Shanghai, 200032
China

Fudan University - Key Laboratory of Public Health

Shanghai, 200032
China

Lijun Jia

Shanghai Jiao Tong University (SJTU) - Department of Oncology

Shanghai
China

Shanghai University of Traditional Chinese Medicine - Cancer Institute ( email )

Shanghai, 200032
China

Zhengfan Jiang

Peking University - State Key Laboratory of Protein and Plant Gene Research

Haidian District, Beijing Summer Palace Road No. 5
Golden Life Sciences Building
Beijing, 100871
China

Rui He (Contact Author)

Fudan University - Department of Immunology ( email )

Shanghai, 200032
Chile

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