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Abrogation of protein phosphatase 6 promotes skin carcinogenesis induced by DMBA

Oncogene volume 34, pages 4647–4655 (2015)Cite this article

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Abstract

Somatic mutations in the gene encoding the catalytic subunit of protein phosphatase 6 (Ppp6c) have been identified in malignant melanoma and are thought to function as a driver in B-raf- or N-ras-driven tumorigenesis. To assess the role of Ppp6c in carcinogenesis, we generated skin keratinocyte-specific Ppp6c conditional knockout mice and performed two-stage skin carcinogenesis analysis. Ppp6c deficiency induced papilloma formation with 7,12-dimethylbenz (a) anthracene (DMBA) only, and development of those papillomas was significantly accelerated compared with that seen following DMBA/TPA (12-O-tetradecanoylphorbol 13-acetate) treatment of wild-type mice. NF-κB activation either by tumor necrosis factor (TNF)-α or interleukin (IL)-1β was enhanced in Ppp6c-deficient keratinocytes. Overall, we conclude that Ppp6c deficiency predisposes mice to skin carcinogenesis initiated by DMBA. This is the first report showing that such deficiency promotes tumor formation in mice.

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Acknowledgements

We thank Dr Hirota Fujiki for critical advice and Dr Yoshikazu Nishino for statistical analyses. We thank Nozomi Sasaki, Kuniko Komuro and Miyuki Ueki for technical assistance. We thank Dr Elise Lamar for English editing. This work was supported by JSPS KAKENHI grant numbers 24591928 to Yoichiro Kakugawa, 25861168 to Kayoko Fukamachi and 22590298 to Hiroshi Shima and by a Nara Women’s University Intramural Grant for Project Research to Toshio Watanabe.

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Author notes

  1. K Hayashi and Y Momoi: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Miyagi, Japan

    K Hayashi, Y Momoi, N Tanuma, H Kato, Y Sakamoto, Y Inoue, M Nomura, M Sakayori, K Fukamachi, Y Kakugawa, Y Yamashita & H Shima

  2. Division of Cancer Molecular Biology, Tohoku University School of Medicine, Miyagi, Japan

    K Hayashi, N Tanuma, H Kato & H Shima

  3. Department of Biological Science, Graduate School of Humanities and Sciences, Nara Women’s University, Nara, Japan

    A Kishimoto, H Ogoh, M Suzuki & T Watanabe

  4. Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Kobe, Japan

    H Kiyonari

  5. Division of Pathology, Miyagi Cancer Center, Miyagi, Japan

    S Ito & I Sato

  6. Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

    A Suzuki & M Nishio

  7. Research Institute for Clinical Oncology, Saitama Cancer Center, Saitama, Japan

    M Suganuma

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  1. K Hayashi
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Correspondence to H Shima.

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Hayashi, K., Momoi, Y., Tanuma, N. et al. Abrogation of protein phosphatase 6 promotes skin carcinogenesis induced by DMBA. Oncogene 34, 4647–4655 (2015). https://doi.org/10.1038/onc.2014.398

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