Loss of polarity protein Par3 in the intestinal epithelium promotes colitis‐associated colorectal cancer progression by damaging tight junction assembly

Author:

Luo Binbin12,Song Linyi12,Chen Limiao1,Cai Yue1,Zhang Mingwei1,Wang Shenyi13ORCID

Affiliation:

1. School of Integrated Traditional Chinese and Western Medicine Anhui University of Chinese Medicine Hefei Anhui China

2. Department of Science and Education The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University Hefei Anhui China

3. Institute of Integrated Chinese and Western Medicine, Anhui Academy of Chinese Medicine Hefei Anhui China

Abstract

AbstractPartitioning defective 3 (Par3) is a polarity protein critical in establishing epithelial cell polarity and tight junctions (TJs). Impaired intestinal epithelial barrier integrity is closely associated with colitis‐associated colorectal cancer (CRC) progression. According to the GEO and TCGA database analyses, we first observed that the expression of Par3 was reduced in CRC patients. To understand how Par3 is related to CRC, we investigated the role of Par3 in the development of CRC using an in vivo genetic approach. Our results show that the intestinal epithelium‐specific PAR3 deletion mice demonstrated a more severe CRC phenotype in the context of azoxymethane/dextran sodium sulfate (AOM/DSS) treatment, with a corresponding increase in tumor number and inflammatory cytokines profile. Mechanistically, loss of Par3 disrupts the TJs of the intestinal epithelium and increases mucosal barrier permeability. The interaction of Par3 with ZO‐1 prevents intramolecular interactions within ZO‐1 protein and facilitates the binding of occludin to ZO‐1, hence preserving TJs integrity. Our results suggest that Par3 deficiency permits pathogenic bacteria and their endotoxins to penetrate the intestinal submucosa and activate TLR4/MyD88/NF‐κB signaling, promoting inflammation‐driven CRC development and that Par3 may be a novel potential molecular marker for the diagnosis of early‐stage CRC.

Publisher

Wiley

Subject

Cancer Research,Molecular Biology

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