THE EPIGENETIC MECHANISM OF HEXAVALENT CHROMIUM CARCINOGENESIS

六价铬致癌的表观遗传机制

• 批准号: 10373379
• 负责人: Chengfeng Yang
• 金额: $ 22.5万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373379
• 关键词: EPIGENETIC; MECHANISM; HEXAVALENT; CHROMIUM; CARCINOGENESIS

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）]是最常见的环境污染物之一，导致肺部和其他污染物 癌症。 CR（VI）癌变的机制尚未阐明。这项研究的长期目标是 确定CR（VI）致癌性的机制，并确定靶标，以更好地治疗和预防 CR（VI）暴露引起的肺癌。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，而是由DNA甲基化介导的组蛋白 翻译后修饰，microRNA和长期非编码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引发的 细胞。基因组印记是指某些基因在父母中表达的表观遗传机制 原来的特定方式，仅限制了它们的表达，仅从两个亲本染色体之一中。许多 研究表明，对表观遗传学和基因组烙印的放松在癌变中起关键作用。 积累的证据表明，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。但是，CR（VI）触发这些表观遗传的机制 修饰基本上仍然未知，这些表观遗传修饰是否在CR（VI）中起因果作用 致癌作用尚不清楚。我们的初步研究发现：（i）慢性CR（VI）暴露会引起类似CSC的样子 性质和细胞恶性转化； （ii）慢性CR（VI）暴露增加了几种HMTases的水平， 在CR（VI）诱导的CSC样性质和细胞转化中起因果作用； （iii）较高水平的H3 在人类的肺癌组织中也检测到抑制性甲基化标记及其相关的HMTase 暴露于铬； （iv）HMTases的上调在慢性CR（VI）引起的慢性CR（VI）中起关键作用 DLK1-DIO3基因组烙印簇的放松管制； （v）miR-494下调在Cr（VI） - 诱导细胞转化； （VI）氧化应激增加了HMTase的水平。基于文学和 我们的初步数据，我们假设：（i）CR（VI）暴露会产生氧化应激，从而增加了水平 hmtases; （ii）HMTases的上调消除DLK1-DIO3基因组烙印群集，该集群 降低miR-494的水平； （iii）miR-494的下调增加了其目标和密钥的水平 CSC因子C-MYC和BMI1，它们产生促进CR（VI）诱导的细胞转化的CSC样性质和 肿瘤发生。这项提出的研究不仅填补了表观遗传学和CR（VI）癌变的知识差距， 但也为氧化应激在CR（VI）癌变中的关键作用提供了新的机械见解。三 提出了目的：目标1：通过下调DLK1-DIO3的miR-494来诱导类似CSC的特性 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：mir-494的下调 通过慢性CR（VI）暴露诱导的HMTases，通过放大DLK1-DIO3基因组印迹群集。目标3： 通过氧化应激通过慢性CR（VI）暴露对HMTase的上调。