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Reactive Oxygen-induced Carcinogenesis Causes Hypermethylation of p16Ink4a and Activation of MAP Kinase

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Abstract

Background

Implantation of foreign materials into mice and humans has been noted to result in the appearance of soft tissue sarcomas at the site of implantation. These materials include metal replacement joints and Dacron vascular grafts. In addition, occupational exposure to nickel has been shown to result in an increased risk of carcinogenesis. The molecular mechanisms of foreign body-induced carcinogenesis are not fully understood. Materials and Methods: In order to gain insight into these mechanisms, we implanted nickel sulfide into wild type C57BL/6 mice as well as a mouse heterozygous for the tumor suppressor gene, p53. Malignant fibrous histiocytomas arose in all mice, and we have characterized the profile of tumor suppressor genes and signal transduction pathways altered in these cells.

Results

All tumors demonstrated hypermethylation of the tumor suppressor gene p16, as well as activation of the mitogen activated protein kinase (MAP kinase) signaling pathway. This knowledge may be beneficial in the prevention and treatment of tumors caused by foreign body implantation.

Conclusions

Oxidative stress induced by nickel sulfide appears to cause loss of p16 and activation of MAP kinase signaling. These findings support the hypothesis of synergistic interactions between MAP kinase activation and p16 loss in carcinogenesis.

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Acknowledgments

This project was funded by a Dermatology Foundation Dermik Laboratories Research Grant, a grant from the American Skin Association, grants from the National Institutes of Health AR02030 and RO1 AR47901, and NIAMS Emory Skin Disease Research Core Center P30 AR42687 (JLA). We acknowledge Drs. Lynda Chin and Jef French for helpful discussion. This project was supported in part by the National Research Service Award (NRSA), HL07842 (RK) from the National Institutes of Health, National Heart, Lung and Blood Institute, grants RO1 ES06501 and ES08252 (MSM) from the National Institute of Environmental Health Sciences and Cancer Center Support Grant P30 CA12197 from the National Cancer Institute, which provided support for the Wake Forest University Analytical Imaging Core Facility, the DNA Synthesis Core Laboratory, and the DNA Sequencing and Gene Analysis Facility. We thank Ms. Elyse Jung for assistance with the automated sequencing. Presented in part at the American Association for Cancer Research 91st Annual Meeting, San Francisco, 2000.

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Authors and Affiliations

  1. Department of Medicine, Dermatology/Oncology, Emory University School of Medicine, 1639 Pierce Drive, WMB 5309, Atlanta, GA, 30322, USA

    Baskaran Govindarajan, Xianhe Bai & Jack L. Arbiser

  2. Department of Medicine, Hematology/Oncology, Emory University School of Medicine, Atlanta, GA, USA

    Robert Klafter

  3. Department of Cancer Biology, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA

    Mark Steven Miller & Melissa Mizesko

  4. Department of Dermatology, Tufts University School of Medicine, Boston, USA

    Claire Mansur

  5. Department of Surgical Research, Children’s Hospital-Harvard Medical School, Boston, MA, USA

    Kenneth LaMontagne Jr

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  1. Baskaran Govindarajan
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Correspondence to Jack L. Arbiser.

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Communicated by J. Folkman.

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Govindarajan, B., Klafter, R., Miller, M.S. et al. Reactive Oxygen-induced Carcinogenesis Causes Hypermethylation of p16Ink4a and Activation of MAP Kinase. Mol Med 8, 1–8 (2002). https://doi.org/10.1007/BF03401997

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