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

描述（由申请人提供）：砷广泛存在于土壤、矿物质、烟雾、被污染的空气和水等环境中。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，砷致癌变的病原学和分子机制仍有待阐明。砷还与非恶性肺血管疾病密切相关。我们的初步结果表明，暴露于砷的肺上皮细胞产生高水平的活性氧（ROS）。砷诱导AKT和ERK1/2活化，HIF-1表达和VEGF转录活化增加。我们假设砷通过ROS信号诱导致癌，而ROS信号反过来调节PI3K、AKT、ERK1/2和HIF-1。为了验证这一假设，我们将执行以下两个目标。在Aim 1中，我们将确定砷在肺上皮细胞中诱导了哪些种类的ROS以及ROS的产生机制，然后确定砷是否通过细胞中ROS的产生来调节PI3K、AKT和ERK的激活。Aim 2将确定砷在诱导肿瘤发生中的作用，以及砷是否通过ROS生成、PI3K、AKT、ERK1/2和HIF-1表达诱导肿瘤发生。我们将研究调节砷诱导肿瘤生长进程的信号通路和分子。在我们了解了砷的致癌作用和潜在机制后，我们将能够在未来开发基于机制的干预措施来预防砷的致癌。与公共卫生有关：砷广泛分布于土壤、矿物质、烟雾、受污染的空气和水等环境中。砷是已知的致癌物质，可诱发人类癌症。然而，砷致癌变的病原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致癌和肿瘤发生相关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在未来开发基于机制的干预措施来预防砷诱导的致癌作用。

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.