The epigenetic mechanism of hexavalent chromium carcinogenesis

六价铬致癌的表观遗传学机制

• 批准号: 9326997
• 负责人: Chengfeng Yang
• 金额: $ 32.92万
• 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/9326997
• 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; Recruitment Activity; Regulation; Role; Stem cells; Tumor Suppressor Genes; Tumor Tissue; Tumorigenicity; United States; Untranslated RNA; Up-Regulation; base; c-myc Genes; cancer cell; cancer stem cell; carcinogenesis; carcinogenicity; cell transformation; chromium hexavalent ion; factor C; genotoxicity; histone methyltransferase; human tissue; imprint; insight; lung cancer prevention; novel; overexpression; pollutant; 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.

项目摘要/摘要 六价铬[Cr(VI)]是引起肺和其他疾病的最常见的环境污染物之一 癌症。铬(VI)的致癌机制尚未阐明。这项研究的长期目标是 确定铬(VI)致癌机制，确定更好的治疗和预防的靶点 暴露于铬(VI)导致的肺癌。表观遗传学指的是基因模式的可遗传变化 不是由DNA序列改变引起的，而是由DNA甲基化、组蛋白介导的表达 翻译后修饰、小RNA和长非编码RNA。肿瘤干细胞是一种癌症。 具有正常干细胞特征的细胞。肿瘤干细胞或肿瘤干细胞样细胞被认为是癌症的始作俑者 细胞。基因组印记是指某些基因在亲本体内表达的表观遗传机制。 来源特定的方式，限制它们仅在两条亲本染色体中的一条染色体上表达。许多 研究表明，表观遗传学和基因组印迹的解除调控在癌症的发生中起着关键作用。 越来越多的证据表明，铬(VI)还会引起表观遗传效应，如改变DNA甲基化和 组蛋白翻译后修饰。然而，铬(VI)触发这些表观遗传的机制 修饰在很大程度上仍不清楚，以及这些表观遗传修饰是否在铬(VI)中起到了因果作用 致癌机制尚不清楚。我们的初步研究发现：(I)慢性铬(VI)暴露诱导CSC样细胞 属性和细胞恶变；(Ii)慢性铬(VI)暴露增加了几种HMTase的水平， 它们在铬(VI)诱导的CSC样特性和细胞转化中起着因果作用；(Iii)更高水平的H3 在人类肺癌组织中也检测到抑制性甲基化标志及其相关的HMTase 铬暴露；(Iv)HMTase上调在慢性铬(VI)暴露中起关键作用 Dlk1-dio3基因组印迹簇的解除调控；(V)miR-494下调在铬(VI)- (6)氧化应激增加HMTase的水平。基于文献和 我们的初步数据，我们假设：(I)暴露于铬(VI)会产生氧化应激，从而增加体内的 HMTase的上调解除了对Dlk1-dio3基因组印迹簇的调控，这是 降低miR-494的水平；和(Iii)下调miR-494的水平增加其靶标和关键基因的水平 CSC因子c-Myc和BMI1，它们产生CSC样特性，促进铬(VI)诱导的细胞转化和 肿瘤发生学。这项拟议的研究不仅填补了表观遗传学和铬(VI)致癌的知识空白， 但也为氧化应激在铬(VI)致癌中的关键作用提供了新的机制见解。三 目标1：通过下调Dlk1-dio3印迹的miR-494诱导CSC样特性 簇及其在铬(VI)诱导的细胞转化和肿瘤发生中的作用目标2：下调miR-494的表达 通过解除对Dlk1-dio3基因组印迹簇的调控，慢性铬(VI)暴露诱导HMTase。目标3： 慢性铬(VI)暴露通过氧化应激上调HMTase的表达。