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Title: Thioredoxin-interacting protein suppresses bladder carcinogenesis.
Authors: Nishizawa, Koji
Nishiyama, Hiroyuki
Matsui, Yoshiyuki  KAKEN_id
Kobayashi, Takashi  kyouindb  KAKEN_id
Saito, Ryoichi
Kotani, Hirokazu  kyouindb  KAKEN_id
Masutani, Hiroshi  kyouindb  KAKEN_id
Oishi, Shinya  kyouindb  KAKEN_id  orcid (unconfirmed)
Toda, Yoshinobu
Fujii, Nobutaka  KAKEN_id
Yodoi, Junji
Ogawa, Osamu  kyouindb  KAKEN_id
Author's alias: 松井, 喜之
小川, 修
Issue Date: 18-Jul-2011
Publisher: Oxford University Press
Journal title: Carcinogenesis
Volume: 32
Issue: 10
Start page: 1459
End page: 1466
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.
Rights: © The Author 2011. Published by Oxford University Press.
This is not the published version. Please cite only the published version.
DOI(Published Version): 10.1093/carcin/bgr137
PubMed ID: 21771725
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