Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA.
Toxicol Sci. 2013 Jul;134(1):26-38. doi: 10.1093/toxsci/kft101. Epub 2013 Jun 7.
Hexavalent chromium [Cr (VI)] is a well-known human carcinogen associated with the increased risk of lung cancer. However, the mechanism underlying the Cr (VI)-induced carcinogenesis remains unclear due to the lack of suitable experimental models. In this study, we developed an in vitro model by transforming nontumorigenic human lung epithelial BEAS-2B cells through long-term exposure to Cr (VI). By utilizing this model, we found that miR-143 expression levels were dramatically repressed in Cr (VI)-transformed cells. The repression of miR-143 led to Cr (VI)-induced cell malignant transformation and angiogenesis via upregulation of insulin-like growth factor-1 receptor (IGF-IR) and insulin receptor substrate-1 (IRS1) expression. Moreover, we found that interleukin-8 is the major upregulated angiogenesis factor induced by Cr (VI) through activation of IGF-IR/IRS1 axis followed by activation of downstream ERK/hypoxia-induced factor-1α/NF-κB signaling pathway. These findings establish a causal role and mechanism of miR-143 in regulating Cr (VI)-induced malignant transformation and tumor angiogenesis.
六价铬[Cr（VI）]是一种众所周知的人类致癌物，与肺癌风险增加有关。然而，由于缺乏合适的实验模型，Cr（VI）诱导的致癌机制仍不清楚。在这项研究中，我们通过长期暴露于 Cr（VI）将非致瘤性人肺上皮 BEAS-2B 细胞转化，从而建立了体外模型。利用该模型，我们发现 miR-143 的表达水平在 Cr（VI）转化的细胞中被显著抑制。miR-143 的抑制导致 Cr（VI）诱导的细胞恶性转化和血管生成，这是通过上调胰岛素样生长因子-1 受体（IGF-IR）和胰岛素受体底物-1（IRS1）表达实现的。此外，我们发现白细胞介素-8 是 Cr（VI）通过激活 IGF-IR/IRS1 轴随后激活下游 ERK/缺氧诱导因子-1α/NF-κB 信号通路诱导的主要上调的血管生成因子。这些发现确立了 miR-143 在调节 Cr（VI）诱导的恶性转化和肿瘤血管生成中的因果作用和机制。
