Colonic expression of glutathione S-transferase alpha 4 and 4-hydroxynonenal adducts is correlated with the pathology of murine colitis-associated cancer

Chronic inflammation-induced oxidative stress is an important driving force for developing colitis-associated cancer (CAC). 4-hydroxynonenal (4-HNE) is a highly reactive aldehyde derived from lipid peroxidation of ω-6 polyunsaturated fatty acids that contributes to colorectal carcinogenesis. Glutathione S-transferase alpha 4 (Gsta4) specifically conjugates glutathione to 4-HNE and thereby detoxifies 4-HNE. The correlation of these oxidative biomarkers with the pathological changes in CAC is, however, unclear. In this study, we investigated the expression of Gsta4 and 4-HNE adducts in azoxymethane/dextran sulfate sodium (AOM/DSS)-induced murine CAC, and analyzed the correlations of 4-HNE and Gsta4 with inflammatory cytokines and the pathological scores in the colon biopsies. Real-time quantitative PCR showed that expression of IL6, TNFα, and Gsta4 sequentially increased in colon tissues for mice treated with DSS for 1, 2, and 3 cycles, respectively. Moreover, immunohistochemical staining showed remarkably increased expression of 4-HNE adducts, Gsta4, TNFα, and IL6 in the colon biopsies after 3 cycles of DSS treatment. Correlation analysis demonstrated that 4-HNE adducts in the colon biopsies were positively correlated with Gsta4 expression. Additionally, the expression of Gsta4 and 4-HNE adducts were strongly correlated with the pathological changes of colon, as well as the expression of TNFα and IL6 in colon tissues. These results provide evidence for the association of oxidative biomarkers Gsta4 and 4-HNE with the pathological changes of CAC and may help developing novel histopathological biomarkers and prevention targets for CAC.