Analysis of arsenic in inducing ROS, signaling pathways, and lung carcinogenesis

描述(申请人提供)：砷在土壤、矿物、烟雾、受污染的空气和水等环境中广泛传播。流行病学研究表明，无机砷暴露可诱发肺癌、皮肤癌、肝癌和膀胱癌。然而，砷致癌的病因学和分子机制仍有待阐明。砷也与非恶性肺血管疾病密切相关。我们的初步结果表明，肺上皮细胞暴露在砷中会产生高水平的活性氧(ROS)。砷可诱导AKT和ERK1/2激活，增加HIF-1表达和VEGF转录激活。我们推测，砷通过ROS信号转导途径诱导肿瘤发生，ROS信号转导途径调控PI3K、AKT、ERK1/2和HIF-1。为了验证这一假设，我们将实现以下两个目标。在目标1中，我们将确定砷诱导的肺上皮细胞中ROS的种类和产生ROS的机制，然后确定砷是否通过产生ROS来调节PI3K、AKT和ERK的激活。目的2确定砷在肿瘤发生中的作用，以及砷是否通过ROS的产生、PI3K、AKT、ERK1/2和HIF-1的表达来诱导肿瘤的发生。我们将研究调控砷诱导肿瘤生长的信号通路和分子。在我们了解了砷的致癌作用和潜在的致癌机制后，我们将能够开发出基于机制的干预措施来预防未来的砷致癌。与公众健康相关：砷在土壤、矿物、烟雾、受污染的空气和水等环境中广泛传播。众所周知，砷是诱发人类癌症的致癌物。然而，砷致癌的病因学和分子机制仍有待阐明。在本研究中，我们计划研究砷在诱导与癌症发生和肿瘤发生相关的信号通路和分子中的作用和机制，并分析这些信号分子在砷诱导肿瘤发生中的作用。这些信息将有助于我们开发基于机制的干预措施，以防止未来砷诱发癌症的发生。

DESCRIPTION (provided by applicant): Arsenic is widely spread in the environment such as soil, minerals, smoke, contaminated air and water. Epidemiologic studies showed that inorganic arsenic exposure induced lung, skin, liver, and bladder cancers. However, the etiology and molecular mechanisms of arsenic in inducing carcinogenesis still remain to be elucidated. Arsenic is also strongly linked to non-malignant lung vascular diseases. Our preliminary results showed that exposure of lung epithelial cells to arsenic produced high levels of reactive oxygen species (ROS). Arsenic induced AKT and ERK1/2 activation, and increased HIF-1 expression and VEGF transcriptional activation. We hypothesize that arsenic induces carcinogenesis through ROS signaling, which in turn regulates PI3K, AKT, ERK1/2, and HIF-1. To test this hypothesis, we will perform the following two aims. In Aim 1, we will identify which species of ROS induced by arsenic and the mechanism of ROS generation in the lung epithelial cells, then determine whether arsenic regulates PI3K, AKT, and ERK activation through ROS generation in the cells. Aim 2 will determine the role of arsenic in inducing tumorigenesis, and whether arsenic induces tumorigenesis through ROS production, PI3K, AKT, ERK1/2, and HIF-1 expression. We will study signaling pathways and molecules that regulate the progression of arsenic-inducing tumor growth. After we learn the effects and the underlying mechanism of arsenic in inducing carcinogenesis, we will be able to develop mechanism-based interventions to prevent carcinogenesis induced by arsenic in the future. PUBLIC HEALTH RELEVANCE: Arsenic is widely spread in the environment such as soil, minerals, smoke, contaminated air and water. Arsenic is known carcinogen for inducing human cancer. However, the etiology and molecular mechanisms of arsenic in inducing carcinogenesis still remain to be elucidated. In this study, we plan to study the roles and mechanism of arsenic in inducing signaling pathways and molecules that are associated with carcinogenesis and tumorigenesis, and to analyze these signaling molecules in arsenic-inducing tumorigenesis. This information will be useful for us to develop mechanism-based interventions to prevent arsenic-inducing carcinogenesis in the future.