Thioredoxin reductase 3 suppression promotes colitis and carcinogenesis via activating pyroptosis and necrosis

Txnrd3 as selenoprotein plays 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.

In the present study, 8-week-old C57BL/6N male Txnrd3-/-, Txnrd3-/ + , Txnrd3 + / + mice, weight 25-30 g, were randomly chosen and each group with 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.

In Txnrd3-/-mice, ulcerative colitis was more severe, the morphological and ultrastructural lesions were also more prominent compared with wild-type mice, accompanied by the significantly increased expression of NLRP3, Caspase1, RIPK3, and MLKL. 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.

Txnrd3 overexpression leads to intracellular calcium outflow and increased ROS, which eventually leads to necrosis and focal death of colon cancer cells, while causing 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.