Expression and regulation of tumor suppressor gene maspin in human bladder cancer

Sugimoto, Shuji; Maass, Nicolai; Takimoto, Yukie; Sato, Katsuhiko; Minei, Sadatsugu; Zhang, Ming; Hoshikawa, Yutaka; Jünemann, Klaus-Peter; Jonat, Walter; Nagasaki, Koichi

doi:10.1016/j.canlet.2003.09.010

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Volume 203, Issue 2 , Pages 209-215, January 2004

Expression and regulation of tumor suppressor gene maspin in human bladder cancer

Shuji Sugimoto
- Department of Urology, University of Kiel, Arnold-Heller-strasse 7, Kiel 24105, Germany
Nicolai Maass
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Kiel, Michaelisstrasse 16, Kiel 24105, Germany
Yukie Takimoto
- Department of Urology, Nihon University, 30-1 Oyaguchikamimachi, Itabashi-ku, Tokyo 173-8610, Japan
Katsuhiko Sato
- Department of Urology, Nihon University, 30-1 Oyaguchikamimachi, Itabashi-ku, Tokyo 173-8610, Japan
Sadatsugu Minei
- Department of Urology, Nihon University, 30-1 Oyaguchikamimachi, Itabashi-ku, Tokyo 173-8610, Japan
Ming Zhang
- Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
Yutaka Hoshikawa
- Department of Gene Expression, Genome Center, Japanese Foundation for Cancer Research, Cancer Institute, 1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo 170-8455, Japan
Klaus-Peter Jünemann
- Department of Urology, University of Kiel, Arnold-Heller-strasse 7, Kiel 24105, Germany
Walter Jonat
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Kiel, Michaelisstrasse 16, Kiel 24105, Germany
Koichi Nagasaki
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Kiel, Michaelisstrasse 16, Kiel 24105, Germany
- Corresponding author. Address: Department of Gene Expression, Genome Center, Japanese Foundation for Cancer Research, Cancer Institute, 1-37-1 Kami-Ikebukuro, Toshima-ku, Tokyo 170-8455, Japan. Tel.: +81-3-5394-3906; fax: +81-3-5394-3926

Received 28 August 2003; received in revised form 1 September 2003; accepted 2 September 2003.

Abstract

Maspin is a member of serine protease inhibitor family with tumor suppressing activity for breast and prostate cancers, acting at the level of tumor invasion and metastasis. However, there have been no published data regarding the role of maspin in human bladder cancer. We evaluated maspin expression in 65 series of bladder cancer samples (22 transurethral resection (TUR) and 43 radical cystectomy) and studied the regulatory mechanism of maspin gene activation in bladder cancer cells. Maspin expression was immunohistochemically detected in four (18.2%) patients with TUR and 22 (51.2%) patients with radical cystectomy whereas no expression was observed in normal transitional cells located at tumor-free area in bladder. The maspin expression was significantly correlated with the development of muscle invasive bladder cancer (P=0.00008). Using a luciferase reporter system, maspin promoter activity was induced in the maspin-positive bladder cancer cell lines as well as maspin-negative RT4 cells. Furthermore, treatment with the DNA methyltransferase inhibitor, 5-aza-2′ deoxycytidine, and histone deacetylase inhibitor, trichostatin A, led to re-expression of maspin in RT4 cells. Our results indicate that maspin may contribute to bladder cancer development and that DNA methylation and histone deacetylation may be important for regulating maspin gene activation in bladder cancer cells.

Keywords: Maspin, Bladder cancer, Transitional cell carcinoma, DNA methylation, Histone deacetylation, 5-Aza-2′deoxycytidine, Trichostatin A