The epigenetic mechanism of hexavalent chromium carcinogenesis

六价铬致癌的表观遗传学机制

• 批准号: 9750769
• 负责人: Chengfeng Yang
• 金额: $ 33.63万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750769
• 关键词: Affect; BMI1 gene; Cancer Etiology; Cells; Characteristics; Chromium; Chromosomes; Chronic; Country; Cultured Cells; DNA Methylation; DNA Modification Methylases; DNA Sequence; Data; Down-Regulation; EZH2 gene; Elements; Environmental Health; Environmental Pollutants; Epigenetic Process; Epithelial Cells; Exposure to; Gene Expression Profile; Genes; Genomic Imprinting; Goals; Heritability; Histone H3; Histones; Human; Impairment; Inherited; Knowledge; Literature; Lung; Lung Neoplasms; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Methylation; MicroRNAs; Modification; Occupational; Oxidative Stress; Parents; Play; Post-Translational Protein Processing; Promoter Regions; Property; Rattus; Reactive Oxygen Species; Regulation; Role; Stem Cell Factor; Stem cells; Tumor Suppressor Genes; Tumor Tissue; United States; Untranslated RNA; Up-Regulation; base; c-myc Genes; cancer cell; cancer stem cell; carcinogenesis; carcinogenicity; cell transformation; chromium hexavalent ion; genotoxicity; histone methyltransferase; human tissue; imprint; insight; lung cancer prevention; novel; overexpression; pollutant; recruit; stem-like cell; tumorigenesis; tumorigenic

PROJECT SUMMARY/ABSTRACT Hexavalent chromium [Cr(VI)] is one of the most common environmental pollutants causing lung and other cancer. The mechanism of Cr(VI) carcinogenesis has not been elucidated. The long-term goal of this study is to determine the mechanism of Cr(VI) carcinogenicity and identify targets for better treatment and prevention of lung cancer resulting from Cr(VI) exposure. Epigenetics refers to heritable changes in the pattern of gene expression that are not caused by changes in DNA sequence, but are mediated by DNA methylation, histone posttranslational modifications, microRNAs and long noncoding RNAs. Cancer stem cells (CSCs) are cancer cells possessing characteristics of normal stem cells. CSCs or CSC-like cells are considered as cancer initiating cells. Genomic imprinting refers to an epigenetic mechanism by which certain genes are expressed in a parent- of-origin-specific manner, restricting their expression from only one of the two parental chromosomes. Many studies demonstrated that deregulation of epigenetics and genomic imprinting plays key roles in carcinogenesis. Accumulating evidence shows that Cr(VI) also causes epigenetic effects such as changing DNA methylation and histone posttranslational modifications. However, the mechanisms by which Cr(VI) triggers these epigenetic modifications remain largely unknown and whether these epigenetic modifications play a causal role in Cr(VI) carcinogenesis are not clear. Our preliminary studies found: (i) Chronic Cr(VI) exposure induces CSC-like property and cell malignant transformation; (ii) Chronic Cr(VI) exposure increases the levels of several HMTases, which play a causal role in Cr(VI)-induced CSC-like property and cell transformation; (iii) Higher levels of H3 repressive methylation marks and their related HMTases are also detected in lung cancer tissues of humans exposed to chromium; (iv) Up-regulation of HMTases plays a crucial role in chronic Cr(VI) exposure-caused deregulation of Dlk1-Dio3 genomic imprinting cluster; (v) miR-494 down-regulation plays a causal role in Cr(VI)- induced cell transformation; and (vi) Oxidative stress increases the levels of HMTases. Based on literature and our preliminary data, we hypothesize: (i) Cr(VI) exposure generates oxidative stress, which increases the levels of HMTases; (ii) Up-regulation of HMTases deregulates the Dlk1-Dio3 genomic imprinting cluster, which decreases the level of miR-494; and (iii) Down-regulation of miR-494 increases the levels of its targets and key CSC factors c-Myc and BMI1, which produce CSC-like property promoting Cr(VI)-induced cell transformation and tumorigenesis. This proposed study not only fills the knowledge gap of epigenetics and Cr(VI) carcinogenesis, but also provides novel mechanistic insights for the crucial role of oxidative stress in Cr(VI) carcinogenesis. Three aims are proposed: Aim 1: Induction of CSC-like property by down-regulating miR-494 of Dlk1-Dio3 imprinting cluster and its role in Cr(VI)-induced cell transformation and tumorigenesis. Aim 2: Down-regulation of miR-494 by chronic Cr(VI) exposure-induced HMTases through deregulating Dlk1-Dio3 genomic imprinting cluster. Aim 3: Up-regulation of HMTases by chronic Cr(VI) exposure through oxidative stress.

项目概要/摘要 六价铬 [Cr(VI)] 是导致肺部和其他疾病的最常见环境污染物之一 癌症。 Cr(VI) 致癌的机制尚未阐明。这项研究的长期目标是 确定 Cr(VI) 致癌机制并确定更好治疗和预防的目标 因接触 Cr(VI) 导致的肺癌。表观遗传学是指基因模式的可遗传变化 不是由 DNA 序列变化引起的表达，而是由 DNA 甲基化、组蛋白介导 翻译后修饰、microRNA 和长非编码 RNA。癌症干细胞（CSC）是癌症 具有正常干细胞特征的细胞。 CSC 或 CSC 样细胞被认为是癌症起始细胞 细胞。基因组印记是指某些基因在亲本中表达的表观遗传机制。 起源特异性方式，限制它们仅从两条亲本染色体之一表达。许多 研究表明，表观遗传学和基因组印记的失调在致癌过程中发挥着关键作用。 越来越多的证据表明 Cr(VI) 还会引起表观遗传效应，例如改变 DNA 甲基化和 组蛋白翻译后修饰。然而，Cr(VI) 触发这些表观遗传的机制 修饰仍然很大程度上未知，以及这些表观遗传修饰是否在 Cr(VI) 中发挥因果作用 致癌机制尚不明确。我们的初步研究发现： (i) 慢性 Cr(VI) 暴露会诱发 CSC 样症状 性状及细胞恶变； (ii) 长期接触 Cr(VI) 会增加多种 HMTase 的水平， 在 Cr(VI) 诱导的 CSC 样特性和细胞转化中起因果作用； (iii) H3 水平较高 在人类肺癌组织中也检测到了抑制性甲基化标记及其相关的 HMTase 接触铬； (iv) HMTase 的上调在慢性 Cr(VI) 暴露引起的过程中起着至关重要的作用 Dlk1-Dio3 基因组印记簇的解除管制； (v) miR-494 下调在 Cr(VI)- 中起因果作用 诱导细胞转化； (vi)氧化应激增加HMT酶的水平。根据文献和 根据我们的初步数据，我们假设：(i) Cr(VI) 暴露会产生氧化应激，从而增加水平 HMT酶； (ii) HMTase 的上调会解除 Dlk1-Dio3 基因组印记簇的调节，从而 降低 miR-494 的水平； (iii) miR-494 的下调会增加其靶标和关键蛋白的水平 CSC 因子 c-Myc 和 BMI1，产生类似 CSC 的特性，促进 Cr(VI) 诱导的细胞转化和 肿瘤发生。这项研究不仅填补了表观遗传学和 Cr(VI) 致癌作用的知识空白， 而且还为氧化应激在 Cr(VI) 致癌过程中的关键作用提供了新的机制见解。三 提出了目标： 目标 1：通过下调 Dlk1-Dio3 印迹的 miR-494 诱导 CSC 样特性 簇及其在 Cr(VI) 诱导的细胞转化和肿瘤发生中的作用。目标 2：下调 miR-494 通过解除 Dlk1-Dio3 基因组印记簇的调节，慢性 Cr(VI) 暴露诱导 HMTases 产生。目标 3： 氧化应激导致慢性 Cr(VI) 暴露上调 HMTase。