Molecular Mechanisms of Nickel-Induced Tumorigenicity

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DESCRIPTION (provided by applicant): The carcinogenicity of nickel compounds has been well documented by studies both in vitro and in vivo. However, the molecular mechanisms by which nickel compounds cause cancer are not well understood. It is accepted that the tumor promotion effects of nickel compounds occur through regulation of gene expression, which is mediated by activated transcription factors. A nuclear factor of activated T cells (NFAT) and nuclear factor-(B (NF(B) are transcription factors, which are believed to play an important role in cancer development. Our preliminary data show that nickel compounds are able to induce activation of NFAT and NF(B in human bronchoepithelial cells. Therefore, the main hypothesis of this proposal is that NFAT and NF(B play a critical role in nickel-induced tumorigenicity in human bronchial epithelial cells (HBECs). The overall goal of this proposal is to study the molecular mechanisms by which nickel compounds mediate carcinogenesis. In particular, this proposal seeks to identify the initiating signaling leading to activation of transcription factors NFAT and NF(B, and their roles in nickel-induced tumorigenicity of human bronchial epithelial cells. Thus, we will investigate this issue in accordance with the following specific aims: 1) To test the hypothesis that reactive oxygen species (ROS) are involved in activation of transcription factor NFAT and NF(B in HBECs in response to nickel compounds; 2) To elucidate the role of NFAT activation in nickel-induced tumorigenicity of HBECs; 3) To test the hypothesis that NF(B transactivation is an important player in nickel-induced tumorigenicity in HBECs; 4) To establish the in vivo effects of nickel compounds on NFAT and NF(B activation by using NFAT and NF(B-luciferase transgenic mice. The significance of the research proposed in this application is that the results derived from the proposed studies will greatly facilitate the understanding of the molecular mechanism of carcinogenic effects of nickel compounds. This study will also provide in vivo models to further investigate the role of NFAT and NF(B activation in nickel-induced carcinogenesis in vivo. Furthermore, it will also help us to determine whether we can use NFAT or NF(B as targets for chemoprevention of nickel-induced carcinogenesis.