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（由申请人提供）：六价铬[Cr(VI)]是导致肺癌和其他癌症的最常见的环境污染物之一。Cr(VI)致癌的机制尚未阐明。本研究的长期目标。旨在确定 Cr(VI) 致癌机制，并确定更好地治疗和预防 Cr(VI) 暴露引起的肺癌的靶标。表观遗传学是指基因表达模式的遗传性变化。癌症干细胞（CSC）不是由 DNA 序列变化引起的，而是由 DNA 甲基化、组蛋白翻译后修饰、微小 RNA 和长非编码 RNA 介导的，是具有正常干细胞或 CSC 样细胞特征的癌细胞。被认为是癌症起始细胞的基因组印记是指某些基因以亲本特异性方式表达的表观遗传机制，限制它们仅从两个亲本之一表达。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) 也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。引发这些表观遗传修饰的因素仍然很大程度上未知，并且这些表观遗传修饰是否在 Cr(VI) 致癌过程中发挥因果作用尚不清楚： (i) 慢性 Cr(VI) 暴露。诱导 CSC 样特性和细胞恶性转化；(ii) 慢性 Cr(VI) 暴露会增加多种 HMTase 的水平，这些 HMTase 在 Cr(VI) 诱导的 CSC 样特性和细胞转化中起因果作用；在接触铬的小鼠和人类的肺癌组织中也检测到了 H3 抑制性甲基化标记及其相关 HMTase 的水平；(iv) HMTase 的上调在慢性疾病中起着至关重要的作用； Cr(VI) 暴露导致 Dlk1-Dio3 基因组印迹簇失调；(v) miR-494 下调在 Cr(VI) 诱导的细胞转化中起因果作用；(vi) 氧化应激增加 HMTase 水平根据文献和我们的初步数据，我们发现：(i) Cr(VI) 暴露会产生氧化应激，从而增加 HMT 酶的水平；(ii) HMT 酶上调；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 CSC 因子 c-Myc 和 BMI1 的水平，从而产生 CSC 样物质；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，而且提供了新的机制。提出了三个目标： 目标 1：通过下调 Dlk1-Dio3 印迹簇的 miR-494 诱导 CSC 样特性及其在 Cr(VI) 中的作用。诱导细胞转化和肿瘤发生 目标 2：慢性 Cr(VI) 暴露诱导的 HMTase 通过解除调节来下调 miR-494。 Dlk1-Dio3 基因组印记簇。目标 3：氧化应激导致的慢性 Cr(VI) 暴露上调 HMTase。