Chromium in carcinogenesis and angiogenesis

铬在致癌和血管生成中的作用

基本信息

批准号：
10328704
负责人：
BingHua Jiang
金额：
$ 30.78万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10328704
关键词：
Chromium carcinogenesis angiogenesis

项目摘要

Hexavalent chromium [Cr(VI)] long-term exposure is associated with human lung cancer. Although there is emerging interest in the mechanism underlying Cr(VI)-induced carcinogenesis, the mechanism and role of Cr(VI) in inducing carcinogenesis still remains to be elucidated. In preliminary studies, we used human peripheral blood mononuclear cells (PBMC cells) from Cr(VI) exposed and control subjects to perform whole genome expression array analysis, and found that IL-8 and CXCL5 are the two most up-regulated genes detected in the exposure group compared with non-exposure subjects. We validated our findings by RT-qPCR and ELISA assay. Additionally, we found that miR-199a suppression and β-catenin upregulation are important for IL-8 and CXCL5 induction. Forced expression of miR-199a and knockdown of IL-8 or CXCL5 inhibited both cell transformation and angiogenesis. These findings are consistent with our results obtained from Cr(VI)- transformed cells and from in vitro studies. Furthermore, we found that β-catenin directly activated IL-8 expression at transcriptional level, while miR-199a directly targets hypoxia-inducible factor 1 (HIF-1) for inhibiting HIF-1 expression. We hypothesize that miR-199a suppression and β-catenin upregulation are important in Cr(VI)-induced tumorigenesis and angiogenesis through induction of IL- 8 and CXCL5 expression. Tumor cell growth and angiogenesis are the important characteristics of carcinogenesis, transformation from normal cells to cancer cells. In order to test this hypothesis, we will perform three specific aims: Aim 1) To determine role of miR-199a suppression and β-catenin upregulation in Cr(VI)-induced cell transformation, and identify the mechanism of IL-8 and CXCL5 elevation. Aim 2) To determine roles of miR-199a, β-catenin, IL-8, and CXCL5 in Cr(VI) transformed cell-induced tumor growth. Aim 3) To determine whether Cr-T cells induce tumor angiogenesis through IL-8 receptors using chimeric tumor model and determine expression levels of IL-8, CXCL5, β-catenin, and miR-199a in peripheral blood mononuclear cells (PBMCs) and plasma, and the possible correlations with Cr(VI) internal exposure doses in workers with occupational Cr(VI) exposure. We will use a combination of molecular approaches, a n animal model, and blood and tissue samples from human subjects to define roles and mechanisms of miR-199a, β- catenin, IL-8, and CXCL5 in Cr(VI)-induced cell transformation, tumor growth, and angiogenesis. These studies will not only help us understand the underlying mechanisms of Cr(VI) in inducing carcinogenesis, but also identify potential new biomarkers for early detection of Cr(VI) exposure of workers in electroplating factories in the future.

长期接触六价铬[Cr(VI)]与人类肺癌有关。人们对 Cr(VI) 诱导致癌机制、Cr(VI) 的机制和作用的兴趣日益浓厚 Cr(VI) 的致癌作用仍有待阐明。在初步研究中，我们使用了人类。来自 Cr(VI) 暴露者和对照受试者的外周血单核细胞 (PBMC 细胞) 进行全基因组表达阵列分析，发现IL-8和CXCL5是上调最多的两个基因我们通过 RT-qPCR 验证了在暴露组与非暴露组中检测到的结果。此外，我们发现 miR-199a 抑制和 β-catenin 上调很重要。 miR-199a 的强制表达和 IL-8 或 CXCL5 的敲低可抑制两者。这些发现与我们从 Cr(VI)- 获得的结果一致。此外，我们发现β-连环蛋白直接激活IL-8。在转录水平表达，而 miR-199a 直接靶向缺氧诱导因子 1 (HIF-1α) 抑制 HIF-1α 表达我们追踪 miR-199a 抑制和 β-连环蛋白。上调对于 Cr(VI) 诱导的 IL-2 诱导的肿瘤发生和血管生成非常重要 8、CXCL5的表达是肿瘤细胞生长和血管生成的重要特征。致癌作用，从正常细胞向癌细胞的转化。为了检验这个假设，我们将。执行三个具体目标：目标 1) 确定 miR-199a 抑制和 β-catenin 上调在 Cr(VI) 诱导细胞转化，并确定 IL-8 和 CXCL5 升高的机制目标 2)。确定 miR-199a、β-catenin、IL-8 和 CXCL5 在 Cr(VI) 转化细胞诱导的肿瘤生长中的作用。 3) 利用嵌合肿瘤确定Cr-T细胞是否通过IL-8受体诱导肿瘤血管生成建立模型并测定外周血中 IL-8、CXCL5、β-catenin 和 miR-199a 的表达水平单核细胞 (PBMC) 和血浆，以及与 Cr(VI) 内照射剂量的可能相关性职业性 Cr(VI) 暴露的工人我们将结合使用分子方法和动物。模型以及人类受试者的血液和组织样本，以确定 miR-199a、β- 的作用和机制连环蛋白、IL-8 和 CXCL5 在 Cr(VI) 诱导的细胞转化、肿瘤生长和血管生成中的作用。研究不仅有助于我们了解 Cr(VI) 诱发致癌的潜在机制，而且还确定了潜在的新生物标志物，用于早期检测电镀工人的 Cr(VI) 暴露未来的工厂。