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. 2020 Aug:85:106610.
doi: 10.1016/j.intimp.2020.106610. Epub 2020 May 27.

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

Sidikjan Ibrahim  1 , Xu Zhu  2 , Xuelai Luo  3 , Yongdong Feng  4 , Jing Wang  5
Affiliations
Free article

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

Sidikjan Ibrahim et al. Int Immunopharmacol. 2020 Aug.
Free article

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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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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