Molecular Mechanism of Arsenic Carcinogenesis

砷致癌的分子机制

• 批准号: 9185317
• 负责人: BingHua Jiang
• 金额: $ 32.94万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-15 至 2017-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9185317
• 关键词: Animal Model; Animals; Arsenic; Binding; Cells; Chronic; DNA Methylation; Development; Down-Regulation; ERBB2 gene; Endothelial Cells; Environmental Exposure; Epithelial Cells; Exposure to; Future; Generations; Human; IL8 gene; Lead; Lung; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of lung; MicroRNAs; Modeling; Molecular; Molecular Biology; NADPH Oxidase; NF-Kappa B p65; NF-kappa B; Oxidative Stress; Play; Prevention; Prevention strategy; Production; Proto-Oncogenes; Reactive Inhibition; Reactive Oxygen Species; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Skin Cancer; T-Lymphocyte; Testing; Tumor Angiogenesis; angiogenesis; arsenic-induced carcinogenesis; base; cancer type; carcinogenesis; cell transformation; exposed human population; hypoxia inducible factor 1; in vivo; novel; novel therapeutics; paracrine; protein expression; public health relevance; receptor; tumor; tumor growth

DESCRIPTION (provided by applicant): Long-term human exposure to inorganic arsenic induces lung and other cancers. The molecular mechanisms of arsenic-induced carcinogenesis remain to be elucidated. Our preliminary studies show that arsenic increases reactive oxygen species (ROS) production, inhibits miR-199 and miR-148 expression, and increases ERBB2, PKM2, NF-kB, HIF-1 and IL-8 expression in lung epithelial cells. Arsenic treatment also induces cell transformation, tumor growth and angiogenesis. We hypothesize that arsenic suppresses miR-199/148 expression through the induction of NOX2, p47phox, ROS; and DNMT1 expression; and miR-199/148 downregulation regulates carcinogenesis (cell transformation, tumor growth, and angiogenesis) through targets: ERBB2 and PKM2/NF-:B. To test this hypothesis, three aims are proposed. Aim 1 will investigate the mechanisms of arsenic in suppressing miR-199 and miR-148 expression through NOX2/p47phox/DNMT1 induction, ROS generation; and miR-199/148 downregulation in turn regulates ERBB2 expression and PKM2/NF-kB interaction. We will investigate: 1) whether arsenic suppresses miR-199 and miR-148 expression through the induction of NOX2, p47Phox, ROS, and DNMT1; 2) whether arsenic induces ERBB2 and PKM2 expression by miR-199/148 downregulation; 3) what regions of PKM2 bind with NF-kB p65 subunit for regulating IL-8 and HIF-1 expression. Aim 2 will investigate the roles of miR-199/148 downregulation in inducing ERBB2 and PKM2/NF-kB expression for regulating cell transformation and tumor growth. We will determine: 1) whether arsenic induces cell transformation and tumor growth through ROS- and DNMT1-induced miR-199/148 downregulation; 2) whether ERBB2 and PKM2 are key direct targets of miR-199/148 for regulating arsenic-induced transformation and tumor growth; and 3) whether PKM2/NF-:B interaction plays an important role. Aim 3 will investigate the mechanisms of arsenic-induced angiogenesis through miR-199/148/ERBB2/PKM2/NF-kB axis for inducing HIF-1 and IL- 8 via paracrine effect using animal models. We will also determine whether secretion of IL-8 will induce tumor angiogenesis through functional IL-8 receptors in endothelial cells (paracrine effect) using chimeric tumor model. This proposed study would provide an important paradigm shift in understanding how miRNAs regulate arsenic-induced tumor growth and angiogenesis through ERBB2 and PKM2/NF-kB axis. Given the important roles of ERBB2, PKM2, NF-kB, HIF-1, and IL-8 in different types of cancers; the proposed studies would be important for future studies on mechanism-based prevention and treatment for arsenic-induced cancer as well as other human cancers.

描述（由申请人提供）：人类长期接触无机砷会诱发肺癌和其他癌症。砷诱发癌变的分子机制仍有待阐明。我们的初步研究表明，砷会增加肺上皮细胞中活性氧（ROS）的产生，抑制miR-199和miR-148的表达，并增加ERBB2、PKM2、NF-kB、HIF-1和IL-8的表达。砷治疗还诱导细胞转化、肿瘤生长和血管生成。我们假设砷通过诱导 NOX2、p47phox、ROS 抑制 miR-199/148 表达；和DNMT1表达； miR-199/148 下调通过靶标 ERBB2 和 PKM2/NF-:B 调节癌发生（细胞转化、肿瘤生长和血管生成）。为了检验这一假设，提出了三个目标。目标1将研究砷通过NOX2/p47phox/DNMT1诱导、ROS生成抑制miR-199和miR-148表达的机制； miR-199/148 下调反过来调节 ERBB2 表达和 PKM2/NF-kB 相互作用。我们将研究：1）砷是否通过诱导NOX2、p47Phox、ROS和DNMT1抑制miR-199和miR-148的表达； 2)砷是否通过下调miR-199/148诱导ERBB2和PKM2表达； 3) PKM2的哪些区域与NF-kB p65亚基结合来调节IL-8和HIF-1的表达。目标 2 将研究 miR-199/148 下调在诱导 ERBB2 和 PKM2/NF-kB 表达以调节细胞转化和肿瘤生长中的作用。我们将确定：1）砷是否通过ROS和DNMT1诱导的miR-199/148下调来诱导细胞转化和肿瘤生长； 2）ERBB2和PKM2是否是miR-199/148调节砷诱导的转化和肿瘤生长的关键直接靶标； 3) PKM2/NF-:B 相互作用是否发挥重要作用。目标 3 将利用动物模型研究砷通过 miR-199/148/ERBB2/PKM2/NF-kB 轴诱导血管生成的机制，通过旁分泌效应诱导 HIF-1 和 IL-8。我们还将使用嵌合肿瘤模型确定IL-8的分泌是否会通过内皮细胞中的功能性IL-8受体（旁分泌效应）诱导肿瘤血管生成。这项拟议的研究将为理解 miRNA 如何通过 ERBB2 和 PKM2/NF-kB 轴调节砷诱导的肿瘤生长和血管生成提供重要的范式转变。鉴于 ERBB2、PKM2、NF-kB、HIF-1 和 IL-8 在不同类型癌症中的重要作用；拟议的研究对于未来基于机制的砷诱发癌症以及其他人类癌症的预防和治疗研究具有重要意义。