2. Academic Validation
  3. PIK3R3 regulates ZO-1 expression through the NF-kB pathway in inflammatory bowel disease

PIK3R3 regulates ZO-1 expression through the NF-kB pathway in inflammatory bowel disease

  • Int Immunopharmacol. 2020 Aug;85:106610. doi: 10.1016/j.intimp.2020.106610.
Sidikjan Ibrahim 1,  Xu Zhu 2,  Xuelai Luo 3,  Yongdong Feng 4,  Jing Wang 5
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: [email protected].
  • 2 Department of Gastrointestinal Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China; Renmin Hospital, Wuhan University, Wuhan 430060, China. Electronic address: [email protected].
  • 3 Department of Gastrointestinal Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: [email protected].
  • 4 Department of Gastrointestinal Surgery Center, Tongji Hospital, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: [email protected].
  • 5 Department of Immunology, Basic Medicine School, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: [email protected].
PMID: 32473571 DOI: 10.1016/j.intimp.2020.106610
Abstract

Background and aims: Inflammatory bowel disease (IBD) are the major risk factor for developing colitis associated Cancer (CAC). Previously, we have reported that Phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3) was overexpressed in colorectal Cancer (CRC), but we don't know the role of PIK3R3 in IBD.

Methods: We investigated the differential expression of PIK3R3 and ZO-1 in IBD patients by using Immunohistochemical (IHC) and Gene Expression Omnibus (GEO) database analysis. Caco-2 cells were exposed to different conditions to assess protein level changes of PIK3R3 and ZO-1. Caco-2 cell monolayers were transfected with PIK3R3/siPIK3R3 to assess transepithelial electrical resistance. Tight junction protein integrity was assessed by immunoblot and immunofluorescence. For further, intestinal permeability and tight junction protein integrity were assessed in animal study to assess the treatment role of PIK3R3 specific inhibitor TAT-N 15 (N15).

Results: PIK3R3 was increased in IBD patients, and negatively controlled the expression of ZO-1. In vitro, PIK3R3 regulates ZO-1 by activating NF-kB pathway. Overexpression of PIK3R3 in Caco-2 cells decreased transepithelial electrical resistance (TEER), an opposite result was observed in siPIK3R3 cells. In animal study, inhibition of PIK3R3 by N15 contributed to amelioration of DSS-induced intestinal permeability. Mice treated with N15 exhibited less disruption of TJs in colon tissues.

Conclusions: PIK3R3 was increased in clinical IBD patients with accompanying disruption of ZO-1 expression. Inhibition of PIK3R3 attenuated DSS-induced IBD symptoms in a mouse model. These findings indicated that PIK3R3 could be a therapeutic target for IBD.

Keywords

Inflammatory bowel disease; PIK3R3; ZO-1.

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