Inflammation suppresses DLG2 expression decreasing inflammasome formation

Abstract

Purpose Loss of expression of DLG2 has been identified in a number of cancers to contribute to the disease by resulting in increased tumor cell proliferation and poor survival. In light of the previous evidence that DLG2 alters the cell cycle and affects proliferation, combined with indications that DLG2 is involved in NLRP3 inflammasome axis we speculated that DLG2 has an immune function. So far, there is no data that clearly elucidates this role, and this study was designed to investigate DLG2 in inflammatory colon disease and in colon cancer as well as its impact on inflammasome induction. Methods The DLG2 expression levels were established in publicly available inflammation, colon cancer and mouse model datasets. The overexpression and silencing of DLG2 in colon cancer cells were used to determine the effect of DLG2 expression on the activation of the inflammasome and subsequent cytokine release. Results The expression of DLG2 is repressed in inflammatory colon diseases IBD and Ulcerative colitis as well as colorectal cancer tissue compared to healthy individuals. We subsequently show that induction with inflammatory agents in cell and animal models results in a biphasic alteration of DLG2 with an initial increase followed by an ensuing decrease. DLG2 overexpression leads to a significant increase in expression of IL1B, IκBζ and BAX, components that result in inflammasome formation. DLG2 silencing in THP1 cells resulted in increased release of IL-6 into the microenvironment which once used to treat bystander COLO205 cells resulted in an increase in STAT3 phosphorylation and an increase proliferating cells and more cells in the G2/M phase. Restoration of DLG2 to the colon resulted in reduced AKT and S6 signaling. Conclusion DLG2 expression is altered in response to inflammation in the gut as well as colon cancer, resulting in altered ability to form inflammasomes. Trial registration NCT03072641.

A genome-wide association study suggests new susceptibility loci for primary antiphospholipid syndrome

“…ESR2 (estrogen receptor 2) (rs932657402, p-value=1.13x10 -6 , OR [95% CI]=0.13 [0.06-0.30]) and HGF (hepatocyte growth factor) (rs75427037, p-value=1.57 x 10 -6 , OR [95% CI]=0.23 [0.12-0.42]), have been associated with thrombotic events [31,32], while EPHA7 (rs117489460, p-value=4.50 x 10 -6 , OR [95% CI]=0.19 [0.09-0.38]) is expressed in vascular endothelial cells and shows higher expression levels during inflammation [33]. Other suggestive loci identified in our meta-analysis have been previously associated with other immune-mediated diseases, such as WNT11 (Wnt family member 11) and DLG2 (discs large MAGUK scaffold protein 2) with inflammatory bowel disease, ANKRD50 (ankyrin repeat domain containing 50) with systemic lupus erythematosus, and PLCL1 (phospholipase C like 1) gene expression with rheumatoid arthritis [34][35][36][37].…”

The central inflammatory regulator IκBζ: induction, regulation and physiological functions

“…Specifically, NFKBIZ has been identified as a novel potential CRC susceptibility gene by exome sequencing of 29 samples from 43 CRC patients that showed familial clustering ( 136 ). The downregulation of NFKBIZ was observed in tumor tissue compared to that in paired healthy mucosa from CRC patients ( 137 ). NFKBIZ mutations are very common in the epithelium of patients with ulcerative colitis but are rarely found in sporadic or colitis-related cancers, suggesting the selection of NFKBIZ-mutant cells during colorectal carcinogenesis ( 138 ).…”

“…Low levels of NFKBIZ expression in LUAD patients have been associated with reduced overall survival ( 142 ). DLG2 is an important tumor suppressor gene, and DLG2 overexpression leads to an increase in the expression of IκBζ ( 137 ).…”

Pooled CRISPR screening of high-content cellular phenotypes using ghost cytometry

“…For example, it is reported that DLG2 is altered in response to inflammation and can activate the formation of NLRP3 inflammasomes. 26 Considering the function of cellular membrane trafficking, STK16 localizes to the Golgi complex and is involved in transporting secretory vesicles, which may indirectly contribute to cytokine production for pro-inflammatory responses. 27 The top-hit gene, BRD2 , is reportedly essential for pro-inflammatory cytokine production in macrophages.…”