Thioredoxin Reductase 3 Suppression Promotes Colitis and Carcinogenesis via Activating Pyroptosis and Necrosis

Abstract Background Txnrd3 as selenoprotein play key roles in antioxidant process and sperm maturation. Inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease are becoming significantly increasing disease worldwide in recent years which are proved relative to diet especially selenium intake. Methods In the present study, 8-week-old C57BL/6N male Txnrd3-/-, Txnrd3-/+, Txnrd3+/+ mice weight 25-30g were randomly chosen and each group 30 mice. Feed 3.5% DSS drinking water and normal water continuously for 7 days. Mouse colon cancer cells (CT26) were cultured in vitro to establish Txnrd3 overexpressed/knocked-down model by cell transfection technology. Morphology and ultrastructure, calcium levels, ROS level, cell death were observed and detected in vivo and vitro. Results Ulcerative colitis was more severe, morphological and ultrastructural lesions were extremely significant in Txnrd3-/- mice based on the fact that expression of NLRP3, Caspase1, RIPK3, MLKL related to pyroptosis and necrosis pathway was significantly increased. Overexpression of Txnrd3 could lead to increased oxidative stress through intracellular calcium outflow induced oxidative stress increase. Followed by necrosis and pyroptosis pathway activation and further inhibit the growth and proliferation of colon cancer cells. Conclusion Txnrd3 overexpression leads to intracellular calcium outflow, endoplasmic reticulum stress, and increased ROS, which eventually leads to necrosis and focal death of colon cancer cells, while Txnrd3-/- mice depth of the crypt deeper, weakened intestinal secretion and immune function. And aggravate the occurrence of ulcerative colitis. The present study lays a foundation for the prevention and treatment of ulcerative colitis and colon carcinoma in clinic treatment.