Published online before print November 30, 2007

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(American Journal of Pathology. 2007;171:1978-1988.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.070741

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

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 β) 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 β-catenin pathway in the RCCs. In the RCCs, dephosphorylated β-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 β-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 β-catenin pathways without the involvement of Wnt signaling for carcinogenesis. Thus, iron-mediated persistent oxidative stress confers an environment for gene amplification.