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Carcinogenesis Advance Access published online on November 21, 2008
Carcinogenesis, doi:10.1093/carcin/bgn255
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Genome-wide analysis identifies a tumor suppressor role for aminoacylase 1 in iron-induced rat renal cell carcinoma

Yi Zhong1,2,{dagger}, Janice Onuki3,{dagger}, Toshinari Yamasaki4, Osamu Ogawa4, Shinya Akasuka1,2 and Shinya Toyokuni1,2,*

1 Department of Pathology and Biological Responses, Graduate School of Medicine, Nagoya University, Showa-ku, Nagoya 466-8550, Japan
2 Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
3 Laboratory and Biochemistry and Biophysics, Butantan Institute, São Paulo, São Paulo, Brazil
4 Department of Urology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507

* All correspondence to: Shinya Toyokuni, M.D., Ph.D.: Department of Pathology and Biological Responses, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Tel: +81 52 744 2086; Fax: +81 52 744 2091; Email: toyokuni{at}med.nagoya-u.ac.jp

A growing number of studies indicate a link between oxidative stress and cancer. We previously developed a rat model of renal cell carcinoma (RCC) induced by ferric nitrilotriacetate (Fe-NTA). Here we performed a genome-wide analysis to study characteristics of genomic alteration and identify putative genes involved in the development of Fe-NTA-induced RCCs. Array-based comparative genomic hybridization (aCGH) analyses revealed a chromosomal loss spanning chromosome 8 in most of the RCCs studied, with a common deletion at 8q31-32, which was confirmed by loss of heterozygosity (LOH) analysis. Studies of gene expression in RCCs or following Fe-NTA treatment revealed globally decreased transcription levels of 34 genes derived from chromosome 8 that are expressed in the kidney. Among them, the aminoacylase 1 (Acy1) gene, which maps to 8q32 and is highly expressed in the kidney, displayed a significantly decreased level of expression in RCCs. Significant amounts of the Acy1 protein were detected in the cytoplasm as well as in the nuclei of renal proximal tubular cells of untreated rats. Transfection of Acy1 into RCC cell lines inhibited proliferation and colony formation on soft agar. An increased number of apoptotic cells were observed following Acy1 transfection. The rat 8q31-32 chromosomal region corresponds to human 3p21.31-24.1, a hot spot where LOH is frequently found in various human cancers. Thus, Fe-NTA-induced renal tumor model is ideal for studying the link between deletions within this region and tumor formation. Our data demonstrate that Acy1 functions as a tumor suppressor in this rat RCC model.

Key Words: Oxidative stress • aminoacylase 1 • ferric nitrilotriacetate • renal cell carcinoma • loss of heterozygosity

{dagger} These authors contributed equally to this work.

Received July 31, 2008; revised October 4, 2008; accepted October 22, 2008.


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