Wang Lin, Zhou Zhi-Hao, Xie Yun-Xia, Liu Wen-Jing, Zhang Rui-Xiang, Jiang Nan, He Ming-Liang, Qiu Jian-Ge, Jiang Bing-Hua
The First Affiliated Hospital of Zhengzhou University, Academy of Medical Science, Zhengzhou University, Zhengzhou 450000, China.
The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, China.
Ecotoxicol Environ Saf. 2023 Jun 19;262:115155. doi: 10.1016/j.ecoenv.2023.115155.
Hexavalent chromium [Cr(VI)] is a well-known environmental carcinogen. Recent studies revealed that chronic exposure of human bronchial epithelial cells (BEAS-2B, B2B) to Cr(VI) activated several signaling pathways and induced cell malignant transformation and tumor growth. However, new mechanisms of Cr(VI) in inducing carcinogenesis remains to be elucidated. This study showed that miR-199a expression levels were significantly lower in Cr(VI)-transformed Cr-T cells. By using the mouse model, the expression levels of miR-199a were significantly decreased in blood samples and lung tissues of mice intranasally exposed to Cr(VI) for 12 weeks compared to the solvent exposure control. Overexpression of miR-199a inhibited tube formation and angiogenesis. C-X-C motif chemokine ligand 8 (CXCL8, IL8) levels were significantly higher in blood samples of Cr (VI)-exposed workers compared to normal workers, and forced expression of miR-199a in the cells suppressed IL8 levels. miR-199a suppression induced expression of hypoxia-inducible factor 1α (HIF-1α) and nuclear factor kappa B (NF-κB) p65 to increase IL8 expression. With animal experiment, the results showed that miR-199a overexpression inhibited tumor growth and angiogenesis through inhibiting IL8, HIF-1α and NF-κB p65 expression in vivo. These results show that miR-199a/IL8 pathway is important in Cr(VI)-induced carcinogenesis and angiogenesis.
六价铬[Cr(VI)]是一种广为人知的环境致癌物。最近的研究表明，人类支气管上皮细胞（BEAS-2B，B2B）长期暴露于Cr(VI)会激活多种信号通路，并诱导细胞恶性转化和肿瘤生长。然而，Cr(VI)诱导致癌作用的新机制仍有待阐明。本研究表明，在Cr(VI)转化的Cr-T细胞中，miR-199a的表达水平显著降低。通过使用小鼠模型，与溶剂暴露对照组相比，经鼻暴露于Cr(VI) 12周的小鼠血液样本和肺组织中miR-199a的表达水平显著降低。miR-199a的过表达抑制了血管生成和血管形成。与正常工人相比，暴露于Cr(VI)的工人血液样本中C-X-C基序趋化因子配体8（CXCL8，IL8）水平显著更高，并且在细胞中强制表达miR-199a可抑制IL8水平。miR-199a的抑制诱导缺氧诱导因子1α（HIF-1α）和核因子κB（NF-κB）p65的表达以增加IL8表达。动物实验结果表明，miR-199a过表达通过在体内抑制IL8、HIF-1α和NF-κB p65的表达来抑制肿瘤生长和血管生成。这些结果表明，miR-199a/IL8通路在Cr(VI)诱导的致癌作用和血管生成中起重要作用。
