The epigenetic mechanism of hexavalent chromium carcinogenesis

六价铬致癌的表观遗传学机制

• 批准号: 9402503
• 负责人: Chengfeng Yang
• 金额: $ 33.55万
• 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/9402503
• 关键词: epigenetic; mechanism; hexavalent; chromium; carcinogenesis

 DESCRIPTION (provided by applicant): 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 mice and 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.

 描述(申请人提供)：六价铬[六价铬]是导致肺癌和其他癌症的最常见的环境污染物之一。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)致癌的机制，并确定更好地治疗和预防由铬(VI)暴露引起的肺癌的靶点。表观遗传学是指基因表达模式的可遗传变化，这些变化不是由DNA序列的改变引起的，而是由DNA甲基化、组蛋白翻译后修饰、microRNAs和长非编码RNAs介导的。肿瘤干细胞(CSCs)是具有正常干细胞特征的癌细胞。CSCs或CSC样细胞被认为是癌症起始细胞。基因组印记指的是一种表观遗传机制，通过这种机制，某些基因以特定于亲本的方式表达，仅限制它们在两条亲本染色体中的一条上表达。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)触发这些表观遗传修饰的机制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)致癌中起因果作用尚不清楚。我们的初步研究发现：(1)慢性铬(VI)暴露可诱导CSC样特性和细胞恶性转化；(2)慢性铬(VI)暴露使多种HMTase的水平升高，这些HMTase在铬(VI)诱导的CSC样特性和细胞转化中起因果作用；(3)在铬暴露的小鼠和人肺癌组织中也检测到高水平的H3抑制甲基化标志及其相关的HMTase；(Iv)HMTase的上调在慢性铬(VI)暴露引起的Dlk1-dio3基因组印迹簇的调控解除中起关键作用；(V)miR-494下调在铬(VI)诱导的细胞转化中起因果作用；(Vi)氧化应激增加HMTase的水平。根据文献和我们的初步数据，我们假设：(I)铬(VI)暴露产生氧化应激，从而增加HMTase的水平；(Ii)HMTase的上调解除对Dlk1-dio3基因组印迹簇的调控，从而降低miR-494的水平；(Iii)miR-494的下调增加其靶标和关键的CSC因子c-Myc和Bmi1的水平，从而产生CSC样属性，促进铬(VI)诱导的细胞转化和肿瘤的发生。这项研究不仅填补了表观遗传学和铬(VI)致癌方面的知识空白，而且为氧化应激在铬(VI)致癌中的关键作用提供了新的机制见解。目的1：通过下调Dlk1-dio3印迹簇miR-494诱导CSC样特性及其在铬(VI)诱导的细胞转化和肿瘤发生中的作用。目的2：通过解除Dlk1-dio3基因组印迹簇的调控，下调慢性铬(VI)暴露诱导的HMTase对miR-494的表达。目的3：慢性铬(VI)暴露通过氧化应激上调HMTase的表达。