Fenton Reaction Induced Cancer in Wild Type Rats Recapitulates Genomic Alterations Observed in Human Cancer

Shinya Akatsuka, Yoriko Yamashita, Hiroki Ohara, Yu Ting Liu, Masashi Izumiya, Koichiro Abe, Masako Ochiai, Li Jiang, Hirotaka Nagai, Yasumasa Okazaki, Hideki Murakami, Yoshitaka Sekido, Eri Arai, Yae Kanai, Okio Hino, Takashi Takahashi, Hitoshi Nakagama, Shinya Toyokuni

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Iron overload has been associated with carcinogenesis in humans. Intraperitoneal administration of ferric nitrilotriacetate initiates a Fenton reaction in renal proximal tubules of rodents that ultimately leads to a high incidence of renal cell carcinoma (RCC) after repeated treatments. We performed high-resolution microarray comparative genomic hybridization to identify characteristics in the genomic profiles of this oxidative stress-induced rat RCCs. The results revealed extensive large-scale genomic alterations with a preference for deletions. Deletions and amplifications were numerous and sometimes fragmented, demonstrating that a Fenton reaction is a cause of such genomic alterations in vivo. Frequency plotting indicated that two of the most commonly altered loci corresponded to a Cdkn2a/2b deletion and a Met amplification. Tumor sizes were proportionally associated with Met expression and/or amplification, and clustering analysis confirmed our results. Furthermore, we developed a procedure to compare whole genomic patterns of the copy number alterations among different species based on chromosomal syntenic relationship. Patterns of the rat RCCs showed the strongest similarity to the human RCCs among five types of human cancers, followed by human malignant mesothelioma, an iron overload-associated cancer. Therefore, an iron-dependent Fenton chemical reaction causes large-scale genomic alterations during carcinogenesis, which may result in distinct genomic profiles. Based on the characteristics of extensive genome alterations in human cancer, our results suggest that this chemical reaction may play a major role during human carcinogenesis.

Original languageEnglish
Article numbere43403
JournalPLoS One
Volume7
Issue number8
DOIs
Publication statusPublished - 2012 Aug 29
Externally publishedYes

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Amplification
Rats
Iron
genomics
neoplasms
Chemical reactions
rats
carcinogenesis
iron overload
Neoplasms
Carcinogenesis
Iron Overload
Oxidative stress
Microarrays
chemical reactions
Tumors
Genes
Cells
mesothelioma
comparative genomic hybridization

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Akatsuka, S., Yamashita, Y., Ohara, H., Liu, Y. T., Izumiya, M., Abe, K., ... Toyokuni, S. (2012). Fenton Reaction Induced Cancer in Wild Type Rats Recapitulates Genomic Alterations Observed in Human Cancer. PLoS One, 7(8), [e43403]. https://doi.org/10.1371/journal.pone.0043403

Fenton Reaction Induced Cancer in Wild Type Rats Recapitulates Genomic Alterations Observed in Human Cancer. / Akatsuka, Shinya; Yamashita, Yoriko; Ohara, Hiroki; Liu, Yu Ting; Izumiya, Masashi; Abe, Koichiro; Ochiai, Masako; Jiang, Li; Nagai, Hirotaka; Okazaki, Yasumasa; Murakami, Hideki; Sekido, Yoshitaka; Arai, Eri; Kanai, Yae; Hino, Okio; Takahashi, Takashi; Nakagama, Hitoshi; Toyokuni, Shinya.

In: PLoS One, Vol. 7, No. 8, e43403, 29.08.2012.

Research output: Contribution to journalArticle

Akatsuka, S, Yamashita, Y, Ohara, H, Liu, YT, Izumiya, M, Abe, K, Ochiai, M, Jiang, L, Nagai, H, Okazaki, Y, Murakami, H, Sekido, Y, Arai, E, Kanai, Y, Hino, O, Takahashi, T, Nakagama, H & Toyokuni, S 2012, 'Fenton Reaction Induced Cancer in Wild Type Rats Recapitulates Genomic Alterations Observed in Human Cancer', PLoS One, vol. 7, no. 8, e43403. https://doi.org/10.1371/journal.pone.0043403
Akatsuka, Shinya ; Yamashita, Yoriko ; Ohara, Hiroki ; Liu, Yu Ting ; Izumiya, Masashi ; Abe, Koichiro ; Ochiai, Masako ; Jiang, Li ; Nagai, Hirotaka ; Okazaki, Yasumasa ; Murakami, Hideki ; Sekido, Yoshitaka ; Arai, Eri ; Kanai, Yae ; Hino, Okio ; Takahashi, Takashi ; Nakagama, Hitoshi ; Toyokuni, Shinya. / Fenton Reaction Induced Cancer in Wild Type Rats Recapitulates Genomic Alterations Observed in Human Cancer. In: PLoS One. 2012 ; Vol. 7, No. 8.
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