Chromium in carcinogenesis and angiogenesis

六价铬[六价铬]长期接触与人类肺癌有关。尽管有 铬(VI)致癌的机制、机制和作用的研究进展 铬(VI)的致癌作用尚不清楚。在初步研究中，我们使用了人类 外周血单核细胞(PBMC细胞)从铬(VI)暴露和对照受试者 基因组表达阵列分析发现，IL-8和CXCL5是上调幅度最大的两个基因 在暴露组与非暴露组进行比较。我们通过RT-qPCR验证了我们的发现 和酶联免疫吸附试验。此外，我们还发现miR-199a抑制和β-catenin上调是很重要的。 用于IL-8和CXCL5的诱导。强制表达miR-199a和敲除IL-8或CXCL5可抑制两者 细胞转化和血管生成。这些发现与我们从六价铬离子中获得的结果是一致的。 转化细胞和来自体外的研究。此外，我们还发现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-1)抑制HIF-1表达。我们假设miR-199a抑制和β-连结蛋白 上调在铬(VI)诱导的肿瘤发生和血管生成中的重要作用 8和CXCL5的表达。肿瘤细胞生长和血管生成是肿瘤的重要特征 癌变，从正常细胞向癌细胞的转化。为了检验这一假设，我们将 实现三个特定目标：目的1)确定miR-199a抑制和β-catenin上调在血管内皮细胞瘤中的作用 CR(VI)诱导的细胞转化，并探讨IL-8和CXCL5升高的机制。目标2) 确定miR-199a、β-连环蛋白、IL-8和CXCL5在铬(VI)转化细胞诱导肿瘤生长中的作用。目标 3)利用嵌合肿瘤模型，研究Cr-T细胞是否通过IL-8受体诱导肿瘤血管生成 建立外周血IL-8、CXCL5、β-连环蛋白和miR-199a的模型并测定其表达水平 单个核细胞(PBMC)和血浆中铬(VI)内照射剂量的关系 职业性铬(VI)接触者。我们将使用分子方法的组合，n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- 连环蛋白、IL-8和CXCL5在铬(VI)诱导的细胞转化、肿瘤生长和血管生成中的作用这些 研究不仅有助于我们了解铬(VI)致癌的潜在机制，而且 也找出潜在的新的生物标志物，以早期检测电镀作业工人的铬(VI)暴露 未来的工厂。

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.