Chronic oxidative stress causes amplification and overexpression of ptprz1 protein tyrosine phosphatase to activate beta-catenin pathway.
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 zeta or receptor tyrosine phosphatase beta) 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 16 approximately 552-fold in the RCCs. Network analysis of the expression revealed the involvement of the beta-catenin pathway in the RCCs. In the RCCs, dephosphorylated beta-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 beta-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 beta-catenin pathways without the involvement of Wnt signaling for carcinogenesis. Thus, iron-mediated persistent oxidative stress confers an environment for gene amplification.
Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Yu-Ting
YT
Liu
Donghao
D
Shang
Shinya
S
Akatsuka
Hiroki
H
Ohara
Khokon Kumar
KK
Dutta
Katsura
K
Mizushima
Yuji
Y
Naito
Toshikazu
T
Yoshikawa
Masashi
M
Izumiya
Kouichiro
K
Abe
Hitoshi
H
Nakagama
Noriko
N
Noguchi
Shinya
S
Toyokuni
D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005290:Ferric Compounds / Q000633:toxicity; D005784:Gene Amplification; D020869:Gene Expression Profiling; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009367:Neoplasm Staging; D009571:Nitrilotriacetic Acid / Q000031:analogs & derivatives / Q000633:toxicity; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D051381:Rats; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000235:genetics*; D051176:beta Catenin / Q000032:analysis / Q000378:metabolism*
D002273:Carcinogens; D005290:Ferric Compounds; D051176:beta Catenin; C516897:Ptprz1 protein, rat; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D009571:Nitrilotriacetic Acid; C020326:ferric nitrilotriacetate