title: Thioredoxin-interacting protein suppresses bladder carcinogenesis.
abstract: Thioredoxin-interacting protein (TXNIP), which has a tumor-suppressive function, is underexpressed in some human cancers. The function of TXNIP in vivo in carcinogenesis is not fully understood. Here, we show TXNIP to be downregulated in human bladder cancer according to grade and stage and also that loss of TXNIP expression facilitates bladder carcinogenesis using a mouse bladder cancer model. N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced bladder cancer was found in 100% of Txnip knockout (KO) mice at week 8 of 0.025% BBN administration but in only 22% of wild-type (WT) mice at the same point. Among growth stimulators, phospho-extracellular signal-regulated kinase (pERK) expression was stronger during bladder carcinogenesis in Txnip-KO mice than in WT mice. We then evaluated TXNIP's effects on ERK activation through various growth stimulators and their receptors. Overexpression of TXNIP in human bladder cancer cells attenuated pERK expression upon stimulation with stromal cell-derived factor-1 (SDF-1) but not with epidermal growth factor or insulin-like growth factor-1. In Txnip-KO mice, immunohistochemical analysis showed enhanced expression of C-X-C chemokine receptor type 4 (CXCR4), the receptor of SDF-1, and of pERK in urothelial cells during BBN-induced bladder carcinogenesis. Finally, subcutaneous injection of CXCR4 antagonist, TF14016, attenuated pERK in urothelial cells and suppressed bladder carcinogenesis. These data indicate that TXNIP negatively regulates bladder carcinogenesis by attenuating SDF-1-CXCR4-induced ERK activation. This signal transduction pathway can be a potent target in preventing or treating bladder cancer.
authors.affiliation: Department of Urology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan. nishizaw@kuhp.kyoto-u.ac.jp
authors.forename: Koji
authors.initials: K
authors.lastname: Nishizawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nishiyama
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Matsui
authors.forename: Takashi
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Saito
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kotani
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Masutani
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Toda
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
authors.forename: Junji
authors.initials: J
authors.lastname: Yodoi
authors.forename: Osamu
authors.initials: O
authors.lastname: Ogawa
mesh_terms: D000368:Aged; D000818:Animals; D015153:Blotting, Western; D002085:Butylhydroxybutylnitrosamine / Q000633:toxicity; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015996:Survival Rate; D013879:Thioredoxins / Q000378:metabolism / Q000502:physiology*; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*
chemical_list: C514936:CXCR4 protein, mouse; D002352:Carrier Proteins; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D012333:RNA, Messenger; D019718:Receptors, CXCR4; C486715:TXNIP protein, human; C445672:Txnip protein, mouse; D002085:Butylhydroxybutylnitrosamine; D013879:Thioredoxins; D048049:Extracellular Signal-Regulated MAP Kinases