Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA; Department of Nutrition and Food Hygiene, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Sci Total Environ. 2022 Sep 10;838(Pt 1):155713. doi: 10.1016/j.scitotenv.2022.155713. Epub 2022 Jun 1.
Chronic exposure to hexavalent chromium compounds [Cr(VI)] is associated with an increased risk of cancers, but the molecular mechanisms remain to be elucidated. In this study, we found that CXCL5 levels in peripheral blood monocytes (PBMCs) and plasma from workers with occupational exposure to Cr(VI) were dramatically upregulated compared to non-exposure healthy subjects, and plasma C-X-C Motif Chemokine Ligand 5 (CXCL5) CXCL5 levels were positively correlated with Cr concentrations in subjects' toenails. Zinc chromate exposed mice showed higher levels of CXCL5 and its receptor CXCR2 in lung tissues, and in PBMCs. Similar CXCL5 upregulation was evident in Cr(VI)-induced transformed (Cr-T) cells with long-term Cr(VI) treatment. Mechanistic studies showed that elevated CXCL5 expression levels were regulated by Cr(VI)-induced histone modifications and DNA hypomethylation, and that the c-Myc/p300 complex was a key upstream regulator of histone H3 acetylation. CXCL5 overexpression promoted Cr(VI)-induced the epithelial to mesenchyme transition (EMT) by upregulating zinc finger E-box binding homeobox 1 (ZEB1) to promote tumor development. Our findings identify a novel mechanism by which CXCL5 is upregulated and promotes EMT and carcinogenesis upon chronic Cr(VI) exposure. Our work also implies that CXCL5 mRNA and protein levels will elevate in PBMCs and serum after occupational Cr(VI) exposure, which may be a potential target and biomarker for cancer prevention and health surveillance among populations exposed to Cr(VI).
慢性接触六价铬化合物（Cr(VI)）会增加癌症的风险，但分子机制仍有待阐明。在这项研究中，我们发现职业性接触 Cr(VI)的工人外周血单核细胞（PBMCs）和血浆中的 CXCL5 水平明显高于非暴露的健康受试者，并且血浆中 C-X-C 基序趋化因子配体 5（CXCL5）水平与受试者脚趾甲中的 Cr 浓度呈正相关。锌铬酸盐暴露的小鼠在肺部组织和 PBMCs 中显示出更高水平的 CXCL5 和其受体 CXCR2。类似的 CXCL5 上调在长期 Cr(VI)处理的 Cr(VI)诱导转化（Cr-T）细胞中也是明显的。机制研究表明，CXCL5 表达水平的升高是由 Cr(VI)诱导的组蛋白修饰和 DNA 低甲基化调节的，c-Myc/p300 复合物是组蛋白 H3 乙酰化的关键上游调节剂。CXCL5 的过表达通过上调锌指 E 盒结合同源盒 1（ZEB1）促进 EMT 来促进 Cr(VI)诱导的 EMT，从而促进肿瘤发展。我们的研究结果确定了一种新的机制，即慢性 Cr(VI)暴露时 CXCL5 被上调并促进 EMT 和致癌作用。我们的工作还表明，职业性 Cr(VI)暴露后，PBMCs 和血清中的 CXCL5 mRNA 和蛋白水平会升高，这可能是 Cr(VI)暴露人群癌症预防和健康监测的潜在靶点和生物标志物。
