Pou3f1 mediates the effect of Nfatc3 on ulcerative colitis-associated colorectal cancer by regulating inflammation

Abstract

Background Ulcerative colitis-associated colorectal cancer (UC-CRC) is an important complication of ulcerative colitis. Pou3f1 (POU class 3 homeobox 1) is a critical regulator for developmental events and cellular biological processes. However, the role of Pou3f1 in the development of UC-CRC is unclear. Methods In vivo, a UC-CRC mouse model was induced by azoxymethane (AOM) and dextran sulfate sodium (DSS). Body weight, colon length, mucosal damage, tumor formation, and survival rate were assessed to determine the progression of UC-CRC. Western blot, quantitative real-time PCR, ELISA, immunohistochemistry, immunofluorescence and TUNEL were performed to examine the severity of inflammation and tumorigenesis. In vitro, LPS-treated mouse bone marrow-derived macrophages (BMDMs) and RAW264.7 cells were used to study the role of Pou3f1 in inflammation. ChIP and luciferase reporter assays were used to confirm the interaction between Nfatc3 and Pou3f1. Results Pou3f1 expression was increased in the colons of UC-CRC mice, and its inhibition attenuated mucosal injury, reduced colon tumorigenesis and increased survival ratio. Knockdown of Pou3f1 suppressed cell proliferation and increased cell death in colon tumors. Both the in vivo and in vitro results showed that Pou3f1 depletion reduced the production of proinflammation mediators. In addition, ChIP and luciferase reporter assays demonstrated that Nfatc3 directly bound with the Pou3f1 promoter to induce its expression. The effect of Nfatc3 on the inflammatory response in macrophages was suppressed by Pou3f1 knockdown. Conclusion Overall, it outlines that Pou3f1 mediates the role of Nfatc3 in regulating macrophage inflammation and carcinogenesis in UC-CRC development.

Roles of macrophages on ulcerative colitis and colitis-associated colorectal cancer

“…Nuclear factor of activated T cell 3 (Nfatc3) targets Pou3f1 to increase its expression, while Pou3f1 can promote inflammation in macrophages. Knockout of Pou3f1 decreased the levels of pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α, and inhibited the tumorigenesis of CAC ( 101 ). G protein-coupled receptor 35 (GPR35) is a soliton G protein-coupled receptor that interacts with sodium-potassium pumps.…”

Update and latest advances in mechanisms and management of colitis-associated colorectal cancer

“…Owing to the known potential of Pou3f1 in regulating immune responses and the immune system, investigators have investigated the role of Pou3f1 in colitis-associated colorectal tumorigenesis. Reduced secretion of inflammatory mediators in macrophages by knocking out Pou3f1 inhibited CAC development[ 33 ]. Ornithine decarboxylase in macrophages promotes colon carcinogenesis by impairing the M1 immune response[ 34 ].…”