Molecular Mechanism of Arsenic Carcinogenesis

砷致癌的分子机制

• 批准号: 9301706
• 负责人: BingHua Jiang
• 金额: $ 4.01万
• 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 2018-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9301706
• 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; Health; 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 Oxygen Species; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Skin Cancer; T-Lymphocyte; Testing; Tumor Angiogenesis; Work; 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; 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）：长期接触无机砷的人会导致肺和其他癌症。砷诱导的癌变的分子机制尚待阐明。我们的初步研究表明，砷增加活性氧（ROS）产生，抑制MIR-199和MIR-148表达，并增加肺上皮细胞中ERBB2，PKM2，NF-KB，HIF-1和IL-8表达。砷处理还诱导细胞转化，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的表达。和DNMT1表达； MiR-199/148下调通过靶标调节致癌作用（细胞转化，肿瘤生长和血管生成）：ERBB2和PKM2/NF-：b。为了检验这一假设，提出了三个目标。 AIM 1将通过NOX2/p47phox/dnmt1诱导，ROS生成来研究砷在抑制miR-199和miR-148表达中的机制； 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miR-199/148下调诱导ERBB2和PKM2表达； 3）PKM2的哪些区域与NF-KB P65亚基结合，用于调节IL-8和HIF-1表达。 AIM 2将研究miR-199/148下调在诱导ERBB2和PKM2/NF-KB表达中调节细胞转化和肿瘤生长的作用。我们将确定：1）砷是否通过ROS-和DNMT1诱导的miR-199/148下调诱导细胞转化和肿瘤生长； 2）ERBB2和PKM2是否是调节砷诱导的转化和肿瘤生长的MiR-199/148的关键直接靶标； 3）PKM2/NF-：B相互作用是否起重要作用。 AIM 3将通过MIR-199/148/ERBB2/PKM2/NF-KB轴研究砷诱导的血管生成的机制，用于使用动物模型通过旁分泌效应诱导HIF-1和IL-8。我们还将确定使用嵌合肿瘤模型在内皮细胞中的功能性IL-8受体（旁分泌作用）中的功能性IL-8受体诱导肿瘤血管生成。这项拟议的研究将在理解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方面提供重要的范式转移。考虑到ERBB2，PKM2，NF-KB，HIF-1和IL-8在不同类型的癌症中的重要作用；拟议的研究对于对基于机制的预防和​​治疗砷诱导的癌症以及其他人类癌症的治疗将很重要。