Suppression of AhR signaling pathway is associated with the down-regulation of UDP-glucuronosyltransferases during BBN-induced urinary bladder carcinogenesis in mice.
Down-regulation of carcinogen detoxifying enzymes might be a critical factor in tumour formation by increasing the carcinogen concentration in the target organ. Previous reports revealed that the expression of UGT1A mRNA is either lost or decreased in certain human cancer tissues, including urinary bladder cancer. To elucidate this down-regulation mechanism, we used an N-nitrosobutyl (4-hydroxybutyl) amine (BBN)-induced mouse urinary bladder carcinogenesis model. Similar to human cancer, the expressions of Ugt1a6, Ugt1a9 and total Ugt1a mRNA in the BBN-induced bladder cancer were markedly decreased compared with those of normal mice. BBN down-regulated the basal Ugt1a mRNA expression in a time-dependent manner and this was reversible in the first 2 weeks of BBN treatment. However, after 4 weeks of BBN treatment the repression became persistent after the cessation of BBN treatment. Aryl hydrocarbon receptor (AhR) regulates the constitutive and inducible expression of Ugt1a mRNA. We found that the constitutive Ugt1a mRNA expression is decreased in the bladder of AhR knockout (KO) mice. Furthermore, BBN-induced Ugt1a down-regulation was lost in AhR KO mice, and the canonical AhR target gene Cyp1a1 was similarly down-regulated by BBN in the bladder. These results demonstrate that BBN repressed Ugt1a mRNA expression via suppression of AhR signaling pathway during BBN-induced carcinogenesis.
Iida
Katsuyuki
K
Department of Urology, Institute of Clinical Medicine, University of Tsukuba, Tennoudai, Tsukuba, Japan.
Mimura
Junsei
J
Itoh
Ken
K
Ohyama
Chikara
C
Fujii-Kuriyama
Yoshiaki
Y
Shimazui
Toru
T
Akaza
Hideyuki
H
Yamamoto
Masayuki
M
D000818:Animals; D002085:Butylhydroxybutylnitrosamine / Q000008:administration & dosage / Q000009:adverse effects*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D000090264:UDP-Glucuronosyltransferase 1A9; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D000099148:UGT1A1 Enzyme
D002085:Butylhydroxybutylnitrosamine; D019363:Cytochrome P-450 CYP1A1; D014453:Glucuronosyltransferase; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme; C000715591:UGT1A9 protein, human; C000715592:Ugt1a9 protein, mouse