Wif1 and Ifitm3 gene expression preferentially altered in the colon mucosa of benzo[a]pyrene pre-treated mice following exposure to dextran sulfate sodium.
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.
Tsukuba Drug Safety, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan. Electronic address: n3-koyama@hhc.eisai.co.jp.
Naoki
N
Koyama
Tsukuba Drug Safety, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
Atsushi
A
Hakura
Tsukuba Drug Safety, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
Naoki
N
Toritsuka
Tsukuba Drug Safety, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
Jiro
J
Sonoda
Tsukuba Drug Safety, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
Yuki
Y
Seki
Biomarkers and Personalized Medicine Core Function Unit, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
Osamu
O
Tohyama
Tsukuba Drug Safety, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
Shoji
S
Asakura
Tsukuba Drug Safety, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
Kyoko
K
Nakano-Ito
Tsukuba Drug Safety, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
Satoru
S
Hosokawa
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity; D003092:Colitis / Q000139:chemically induced*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000503:physiopathology*; D016264:Dextran Sulfate / Q000633:toxicity*; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009153:Mutagens / Q000633:toxicity
D048868:Adaptor Proteins, Signal Transducing; D016326:Extracellular Matrix Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009153:Mutagens; C118544:Wif1 protein, mouse; C462181:fragilis protein, mouse; D001564:Benzo(a)pyrene; D016264:Dextran Sulfate
Benzo[a]pyrene; Colon; Dextran sulfate sodium; Gene expression; Ifitm3; Wif1