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

Baskaran Govindarajan,Melissa Mizesko,Xianhe Bai,Mark Steven Miller,Claire Mansur,Robert Klafter,Kenneth Lamontagne,Jack L Arbiser

doi:10.1007/bf03401997

Abstract

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. 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. 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. 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.

Highlights

Oxidative stress is thought to be a major contributor to multiple forms of carcinogenesis, including chemical, ultraviolet, and radiation-induced cancers [1,2,3,4]
Inoculation of nickel sulfide into the thigh muscle of both wild type and p53 heterozygous mice lead to development of sarcomas (Fig. 1)
Cell lines derived from these tumors were analyzed for the activation of the MAP kinase and phosphoinositol-3 kinase (PI-3 K) pathways through Western analysis of cell lysates with antibodies specific for phosphosp cific MAP kinase and phospho-specific Akt, respectively [26]

Summary

Introduction

Oxidative stress is thought to be a major contributor to multiple forms of carcinogenesis, including chemical-, ultraviolet-, and radiation-induced cancers [1,2,3,4]. Phagocytosis and solubilization of nickel sulfide have been established as necessary steps in the generation of nickel-induced tumors [9,10] Both soluble and insoluble forms of nickel have been implicated in human cancer, with the generation of soluble Ni2ϩ thought to be a common factor [11]. 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

Methods

Results

Conclusion