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Updated: May 30, 2026
11:02
Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development
Published on: October 30, 2013
Thioredoxin-interacting protein suppresses bladder carcinogenesis.
Koji Nishizawa1, Hiroyuki Nishiyama, Yoshiyuki Matsui
1Department of Urology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan. nishizaw@kuhp.kyoto-u.ac.jp
Carcinogenesis
|July 21, 2011
Summary
Thioredoxin-interacting protein (TXNIP) loss accelerates bladder cancer by enhancing SDF-1/CXCR4 signaling and ERK activation. Restoring TXNIP function may offer a new therapeutic strategy for bladder cancer prevention and treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Thioredoxin-interacting protein (TXNIP) exhibits tumor-suppressive functions and is often underexpressed in human cancers.
- The in vivo role of TXNIP in carcinogenesis, particularly in bladder cancer, remains incompletely understood.
- TXNIP downregulation correlates with bladder cancer grade and stage.
Purpose of the Study:
- To investigate the role of TXNIP in bladder carcinogenesis in vivo.
- To elucidate the molecular mechanisms by which TXNIP influences bladder cancer development.
- To identify potential therapeutic targets for bladder cancer based on TXNIP's function.
Main Methods:
- Utilized a mouse model of N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced bladder cancer, comparing wild-type (WT) and Txnip knockout (KO) mice.
- Assessed bladder tumor incidence and progression at week 8 of BBN administration.
- Examined the expression of phospho-extracellular signal-regulated kinase (pERK), C-X-C chemokine receptor type 4 (CXCR4), and its ligand stromal cell-derived factor-1 (SDF-1) using immunohistochemistry.
- Investigated the effect of TXNIP overexpression on ERK activation in human bladder cancer cells stimulated with growth factors.
- Evaluated the therapeutic potential of a CXCR4 antagonist (TF14016) in vivo.
Main Results:
- Txnip knockout mice exhibited 100% bladder cancer incidence by week 8 of BBN administration, compared to 22% in WT mice.
- Loss of TXNIP expression led to enhanced phospho-extracellular signal-regulated kinase (pERK) expression during bladder carcinogenesis.
- TXNIP overexpression attenuated pERK expression induced by SDF-1, but not by EGF or IGF-1, in human bladder cancer cells.
- Txnip-KO mice showed increased expression of CXCR4 and pERK in urothelial cells during BBN-induced carcinogenesis.
- Administration of a CXCR4 antagonist suppressed pERK activation and inhibited bladder carcinogenesis in mice.
Conclusions:
- TXNIP negatively regulates bladder carcinogenesis by attenuating SDF-1/CXCR4-induced ERK activation.
- The SDF-1/CXCR4/ERK signaling pathway is a critical mediator of TXNIP's tumor-suppressive function in the bladder.
- Targeting the SDF-1/CXCR4 pathway presents a promising strategy for preventing or treating bladder cancer.
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