title: Carbonic anhydrase 2 is a novel invasion-associated factor in urinary bladder cancers.
abstract: Rat bladder cancer is nearly always papillary non-invasive urothelial carcinoma (UC). To establish an animal model mimicking invasive UC that arises from papillary non-invasive UC in the bladder, male human c-Ha-ras proto-oncogene transgenic rats (Hras128) were treated with 0.05% N-butyl-N-(hydroxybutyl)nitrosameine (BBN) in their drinking water and/or 0.1% phenylethyl isothiocyanate (PEITC) in their diet as follows: BBN (8 weeks)→PEITC (8 weeks); PEITC (8 weeks)→BBN (8 weeks); BBN alone (16 weeks); PEITC alone (16 weeks); and no treatment. At the end of week 16, the highest incidence of invasive UC was observed in the BBN→PEITC group. Therefore, we used Hras128 rats treated with BBN followed by PEITC as a model of invasive bladder cancer to identify invasion-associated proteins. Proteome analysis was performed to compare the protein profiles of invasive and non-invasive UC in Hras128 rats. We identified 49 proteins that were either overexpressed or underexpressed in invasive UC but not in non-invasive UC. Immunohistochemical analysis of carbonic anhydrase 2 (CA2), an overexpressed protein, showed that the relative number of CA2-positive UC was significantly higher for invasive UC compared to non-invasive UC in rats. Moreover, the incidence of CA2-positive cancers was also significantly higher for human muscle-invasive bladder cancer (MIBC) compared to non-MIBC (NMIBC) and was positively associated with the progression of NMIBC. Our findings indicate that CA2 is an invasion-associated factor and suggest that it could serve as a potential therapeutic molecular target for bladder cancers.
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.|Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tachibana
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Min
authors.initials: M
authors.lastname: Gi
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.|Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Shotaro
authors.initials: S
authors.lastname: Yamano
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Fujioka
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Anna
authors.initials: A
authors.lastname: Kakehashi
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.|Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yukiyoshi
authors.initials: Y
authors.lastname: Hirayama
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.|Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Koyama
authors.affiliation: Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tamada
authors.affiliation: Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Nakatani
authors.affiliation: Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Wanibuchi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D030801:Animals, Genetically Modified; D024402:Carbonic Anhydrase II / Q000378:metabolism*; D002273:Carcinogens / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D017879:Isothiocyanates / Q000633:toxicity; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology*; D009602:Nitrosamines / Q000633:toxicity; D000090063:Proto-Oncogene Mas; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D051381:Rats; D001743:Urinary Bladder / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000473:pathology*
chemical_list: D002273:Carcinogens; D017879:Isothiocyanates; C000715470:MAS1 protein, human; D009602:Nitrosamines; D000090063:Proto-Oncogene Mas; C058305:phenethyl isothiocyanate; D016283:Proto-Oncogene Proteins p21(ras); D024402:Carbonic Anhydrase II
keywords: Carbonic anhydrase 2; Hras128 rats; N-butyl-N-(hydroxybutyl)nitrosameine; invasion-associated factor; invasive urinary bladder cancer