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Carcinogenesis Advance Access published online on January 12, 2008
Carcinogenesis, doi:10.1093/carcin/bgn006
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Fez1/Lzts1 deficient mice are more susceptible to N-butyl-N-(4-hydroxybutil) nitrosamine (BBN) carcinogenesis

Raffaele Baffa1, Matteo Fassan1, Cinzia Sevignani2, Andrea Vecchione1, Hideshi Ishii2, Enrico Giarnieri1, Renato V. Iozzo3, Leonard G. Gomella1 and Carlo M. Croce4

1 Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
2 Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
3 Department of Pathology, Anatomy and Cell Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
4 Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, OH

Correspondence: Raffaele Baffa, M.D. Department of Urology, Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, Room 526A, Philadelphia, Pennsylvania 19107, United States. Phone: (215) 955-9072 Fax: (215) 503-2627 R_Baffa{at}mail.jci.tju.edu

Fez1/Lzts1 (Lzts1) is a tumor suppressor gene that is frequently altered in human cancers of different histotypes. We have previously reported that LZTS1 is down-regulated in high-grade bladder cancer and that its restoration suppresses tumorigenicity in urothelial carcinoma cells. To further investigate the role of LZTS1 in the development of bladder cancer, we utilized heterozygous and nullizygous Lzts1 mice in a chemically-induced carcinogenesis model. Fifty-eight mice consisting of 25 Lzts1, 17 Lzts1, and 16 Lzts1–/–, were treated with N-butyl-N-(4-hydroxybutil) nitrosamine (BBN). Results showed that there was a significant increase in neoplastic lesions in the Lzts1 (82.3%) and Lzts1–/– (93.8%) vs. Lzts1 (8.0%) mice after BBN treatment. No difference in cancer incidence between Lzts1 and Lzts1–/– was observed. Collectively, these findings indicate that loss of one or both LZTS1 alleles hampers the normal defenses of urothelial cells against carcinogens, favoring bladder cancer development. Therefore, LZTS1 may become an excellent target for gene therapy in advanced bladder carcinoma.

Key Words: Bladder cancer • FEZ1/LZTS1 • BBN • mouse model

Received July 20, 2007; revised November 19, 2007; accepted December 20, 2007.


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