Department of Urology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Thioredoxin interacting protein (TXNIP), which has a tumor-suppressive function, is under-expressed in some human cancers. The function of TXNIP in vivo in carcinogenesis is not fully understood. Here, we show TXNIP to be down-regulated 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 knock-out (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-ERK (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. Over-expression of TXNIP in human bladder cancer cells attenuated pERK expression upon stimulation with stromal cell-derived factor-1 (SDF-1), but not with EGF or IGF-1. In Txnip-KO mice, immunohistochemical analysis showed enhanced expression of 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.
Written by:
Nishizawa K, Nishiyama H, Matsui Y, Kobayashi T, Kotani H, Masutani H, Oishi S, Saito R, Toda Y, Fujii N, Yodoi J, Ogawa O. Are you the author?
Reference: Carcinogenesis. 2011 Jul 18. Epub ahead of print.
doi: 10.1093/carcin/bgr137
PubMed Abstract
PMID: 21771725
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