Published online before print November 30, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.070741

Accepted for publication September 6, 2007.

Article

Chronic Oxidative Stress Causes Amplification and Overexpression of ptprz1 Protein Tyrosine Phosphatase to Activate -Catenin Pathway

Yu-Ting Liu^*, Donghao Shang, Shinya Akatsuka^*, Hiroki Ohara^*, Khokon Kumar Dutta^*, Katsura Mizushima, Yuji Naito, Toshikazu Yoshikawa, Masashi Izumiya^¶, Kouichiro Abe^¶, Hitoshi Nakagama^¶, Noriko Noguchi^||, and Shinya Toyokuni^*@

From the Departments of Pathology and Biology of Diseases,* and Urology, Graduate School of Medicine, Kyoto University, Kyoto; Medical Proteomics, and Inflammation and Immunology, Graduate School of Medicine, Kyoto Prefectural University of Medicine, Kyoto; the Biochemistry Division,^¶ National Cancer Center Research Institute, Tokyo; and the Science and Engineering Research Institute,^|| Doshisha University, Kyoto, Japan

^@ To whom correspondence should be addressed. E-mail: toyokuni{at}path1.med.kyoto-u.ac.jp.

	Abstract

Ferric nitrilotriacetate induces oxidative renal tubular damage via Fenton-reaction, which subsequently leads to renal cell carcinoma (RCC) in rodents. Here, we used gene expression microarray and array-based comparative genomic hybridization analyses to find target oncogenes in this model. At the common chromosomal region of amplification (4q22) in rat RCCs, we found ptprz1, a tyrosine phosphatase (also known as protein tyrosine phosphatase or receptor tyrosine phosphatase ) highly expressed in the RCCs. Analyses revealed genomic amplification up to eightfold. Despite scarcity in the control kidney, the amounts of PTPRZ1 were increased in the kidney after 3 weeks of oxidative stress, and mRNA levels were increased 16552-fold in the RCCs. Network analysis of the expression revealed the involvement of the -catenin pathway in the RCCs. In the RCCs, dephosphorylated -catenin was translocated to nuclei, resulting in the expression of its target genes cyclin D1, c-myc, c-jun, fra-1, and CD44. Furthermore, knockdown of ptprz1 with small interfering RNA (siRNA), in FRCC-001 and FRCC-562 cell lines established from the induced RCCs, decreased the amounts of nuclear -catenin and suppressed cellular proliferation concomitant with a decrease in the expression of target genes. These results demonstrate that chronic oxidative stress can induce genomic amplification of ptprz1, activating -catenin pathways without the involvement of Wnt signaling for carcinogenesis. Thus, iron-mediated persistent oxidative stress confers an environment for gene amplification.