Benzo[a]pyrene (BP) is highly mutagenic and yet does not lead to
tumor development in the murine colon. We recently reported the generation of colonic
tumors one week
after treatment with BP followed by
dextran sulfate sodium (DSS), a
colitis-inducer. In this BP/DSS model, male CD2F1 mice were treated orally with BP at 125 mg/kg/day for 5 days, followed by 4% DSS in
drinking water for one week. There has been no report so far on the molecular mechanisms involved in
tumor development in this model. In the present study, we performed global gene expression analysis on the colonic mucosae obtained from BP-exposed mice one week
after treatment with DSS and those treated with the vehicle, BP, or DSS alone. Global gene expression analysis revealed that there were 563 genes preferentially altered (≥2-fold vs vehicle group) in the colonic mucosae exposed to both BP and DSS. Furthermore, comparative gene expression analysis combined with Ingenuity Pathway Analysis™ identified 2 genes associated with Wnt/β-
catenin signaling pathway that were preferentially up-regulated (≥2-fold vs vehicle group) when BP and DSS were treated in combination in the distal part (site of predilection for
tumor induction) of the colonic mucosae, especially in colonic
tumors: WNT inhibitory factor 1 (Wif1; 14.6-fold increase) and
interferon induced
membrane protein 3 (Ifitm3; 5.7-fold increase). In colonic
tumors, expression of Wif1 and Ifitm3
proteins were both confirmed by western blot analysis. These findings suggest that these genes are associated with rapid induction of colonic
tumors in mice after exposure to BP/DSS, providing insights into the mechanisms of the BP/DSS short-term colon
carcinogenesis.