The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450052, Henan, China.
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, USA.
Toxicol Appl Pharmacol. 2019 Sep 1;378:114603. doi: 10.1016/j.taap.2019.114603. Epub 2019 May 29.
Hexavalent chromium [Cr(VI)] is a known occupational and environmental contaminant and carcinogen, but new mechanisms of Cr(VI)-induced carcinogenesis remain to be elucidated. In this study, we found that expression of miR-143 is decreased, whereas that of Interleukin 6 (IL-6) is increased in blood samples of Cr(VI)-exposing workers compared with corresponding unexposed workers. In addition, IL-6 was increased in human bronchial epithelial cells (BEAS-Cr) exposed to Cr(VI) compared with unexposed BEAS-2B cells. To further investigate the mechanisms by which Cr(VI) promotes these changes, we assessed the effects of miR-143 on gene expression and found that miR-143 suppressed expression of IL-6, HIF-1α and NF-κB p65, and that inhibiting miR-143 promoted expression of IL-6, HIF-1α and NF-κB p65. Interestingly, IL-6 regulated expression of HIF-1α, and HIF-1α transcriptionally regulated expression of IL-6. Experiments in animals showed that miR-143 inhibited tumor growth and angiogenesis by regulating IL-6/HIF-1α and downstream signaling pathways in vivo. These outcomes support the hypothesis that the miR-143/IL-6/HIF-1α pathway functions to regulate Cr(VI)-induced carcinogenesis.
六价铬（Cr(VI)）是一种已知的职业和环境污染物及致癌物，但 Cr(VI)诱导致癌的新机制仍有待阐明。在本研究中，我们发现与相应的未暴露工人相比，暴露于 Cr(VI)的工人的血液样本中 miR-143 的表达降低，而白细胞介素 6（IL-6）的表达增加。此外，与未暴露的 BEAS-2B 细胞相比，暴露于 Cr(VI)的人支气管上皮细胞（BEAS-Cr）中 IL-6 增加。为了进一步研究 Cr(VI)促进这些变化的机制，我们评估了 miR-143 对基因表达的影响，发现 miR-143 抑制了 IL-6、HIF-1α 和 NF-κB p65 的表达，而抑制 miR-143 则促进了 IL-6、HIF-1α 和 NF-κB p65 的表达。有趣的是，IL-6 调节 HIF-1α 的表达，而 HIF-1α 转录调节 IL-6 的表达。动物实验表明，miR-143 通过调节体内的 IL-6/HIF-1α 和下游信号通路抑制肿瘤生长和血管生成。这些结果支持了 miR-143/IL-6/HIF-1α 通路在调节 Cr(VI)诱导的致癌作用中的假说。
