Ninjurin1 deficiency differentially mitigates colorectal cancer induced by azoxymethane and dextran sulfate sodium in male and female mice

Abstract

This study investigated the role of Ninjurin1 (Ninj1), encoding a small transmembrane protein, in colitis-associated colon tumorigenesis in relation to sex hormones. Male and female wild-type (WT) and Ninj1 knockout (KO) mice were treated with azoxymethane (AOM) and dextran sulfate sodium (DSS), with or without testosterone propionate (TP). At week 2 (acute colitis stage), Ninj1 KO exhibited an alleviation in the colitis symptoms in both male and female mice. The M2 macrophage population increased and CD8⁺ T cell population decreased only in the female Ninj1 KO than in the female WT AOM/DSS group. In the female AOM/DSS group, TP treatment exacerbated colon shortening in the Ninj1 KO than in the WT. At week 13 (tumorigenesis stage), male Ninj1 KO mice had fewer tumors, but females showed similar tumors. In the WT AOM/DSS group, females had more M2 macrophages and fewer M1 macrophages than males, but this difference was absent in Ninj1 KO mice. In the Ninj1 KO versus WT group, the expression of pro-inflammatory mediators and Ho-1 and CD8⁺ T cell populations decreased in both female and male Ninj1 KO mice. In the WT group, M2 macrophage populations were increased by AOM/DSS treatment and decreased by TP treatment. However, neither treatment changed the cell populations in the Ninj1 KO group. These results suggest that Ninj1 is involved in colorectal cancer development in a testosterone-dependent manner, which was different in male and female. This highlights the importance of considering sex disparities in understanding Ninj1's role in cancer pathogenesis.

Keywords: NINJ1 protein; colitis‐associated neoplasms; sex characteristics; testosterone propionate.