Molecular Mechanisms of Nickel-Induced Tumorigenicity

描述(申请人提供)：镍化合物的致癌性已经通过体外和体内研究得到了很好的证明。然而，镍化合物致癌的分子机制还不是很清楚。人们普遍认为镍化合物的促癌作用是通过调节基因表达而实现的，而基因表达调控是由激活的转录因子介导的。活化T细胞核因子(NFAT)和核因子-B(NF(B))是转录因子，被认为在肿瘤的发生发展中起重要作用。我们的初步数据显示，镍化合物能够诱导人支气管上皮细胞中NFAT和NF(B)的激活。因此，这一建议的主要假设是NFAT和NF(B)在镍诱导的人支气管上皮细胞(HBECs)的致瘤性中起关键作用。这项提议的总体目标是研究镍化合物介导致癌的分子机制。特别是，这项建议试图确定导致转录因子NFAT和NF(B)激活的起始信号，以及它们在镍诱导的人支气管上皮细胞致癌中的作用。因此，我们将根据以下特定目的调查此问题：1)验证活性氧基团(ROS)参与激活转录因子NFAT及NF(B)在镍化合物诱导的HBECs致瘤性中的作用的假设；2)阐明NFAT激活在镍诱导的HBECs致瘤性中的作用；3)测试NF(B反式激活是镍诱导的HBECs致癌的一个重要角色)的假设；4)通过使用NFAT和NF(B-荧光素酶)转基因小鼠，建立镍化合物对NFAT和NF(B)激活的体内影响。本申请中提出的研究的意义在于，建议的研究结果将极大地有助于理解镍化合物致癌作用的分子机制。本研究还将为进一步研究NFAT和NF(B)的激活在镍诱导的体内致癌中的作用提供体内模型。此外，它还将帮助我们确定是否可以使用NFAT或NF(B)作为镍诱导的致癌的化学预防的靶点。

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.