Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KY 40503, USA.
J Environ Pathol Toxicol Oncol. 2013;32(1):41-51. doi: 10.1615/jenvironpatholtoxicoloncol.2013007097.
Tungsten carbide-cobalt (WC-Co) nanoparticle composites have wide applications because of their hardness and toughness. WC-Co was classified as "probably carcinogenic" to humans by the International Agency for Research on Cancer (IARC) in 2003. It is believed that the toxicity and carcinogenesis of WC-Co is associated with particle size. Recent studies demonstrated that the tumor suppressor gene programmed cell death 4 (PDCD4) and its upstream regulator miR-21 have been considered as oncogenes for novel cancer prevention or anticancer therapies. The present study examined the effects of WC-Co nanoparticles on miR-21-PDCD4 signaling in a mouse epidermal cell line (JB6 P+). The results showed that (i) exposure of JB6 cells to WC-Co stimulated a increase of miR-21 generation; (ii) WC-Co also caused inhibition of PDCD4, a tumor suppressor protein and downstream target of miR-21, expression in JB6 cells; (iii) inhibition of ERKs with ERK inhibitor U0126 significantly reversed WC-Cominus;induced PDCD4 inhibition, but inhibition of p38 with p38 inhibitor SB203580 did not; and (iv) ROS scavengers, N-acetyl-L-cysteine and catalase, blocked the inhibitory effect of WC-Co on PDCD4 expression, while superoxide dismutase promoted the inhibitory effect. These findings demonstrate that WC-Co nanoparticles induce miR-21 generation, but inhibit PDCD4 production, which may be mediated through ROS, especially endogenous H2O2, and ERK pathways. Unraveling the complex mechanisms associated with these events may provide insights into the initiation and progression of WC-Co-induced carcinogenesis.
碳化钨-钴（WC-Co）纳米粒子复合材料由于其硬度和韧性而具有广泛的应用。2003 年，国际癌症研究机构（IARC）将 WC-Co 归类为“可能对人类致癌”。据信，WC-Co 的毒性和致癌性与其颗粒大小有关。最近的研究表明，肿瘤抑制基因程序性细胞死亡 4（PDCD4）及其上游调节剂 miR-21 已被认为是新型癌症预防或抗癌治疗的致癌基因。本研究探讨了 WC-Co 纳米颗粒对小鼠表皮细胞系（JB6 P+）中 miR-21-PDCD4 信号通路的影响。结果表明：（i）暴露于 WC-Co 的 JB6 细胞刺激 miR-21 的产生增加；（ii）WC-Co 还导致 JB6 细胞中肿瘤抑制蛋白和 miR-21 的下游靶标 PDCD4 的表达受到抑制；（iii）用 ERK 抑制剂 U0126 抑制 ERKs 可显著逆转 WC-Co 引起的 PDCD4 抑制，但用 p38 抑制剂 SB203580 抑制 p38 则没有；（iv）ROS 清除剂 N-乙酰-L-半胱氨酸和过氧化氢酶阻断了 WC-Co 对 PDCD4 表达的抑制作用，而超氧化物歧化酶则促进了抑制作用。这些发现表明，WC-Co 纳米颗粒诱导 miR-21 的产生，但抑制 PDCD4 的产生，这可能是通过 ROS 介导的，特别是内源性 H2O2 和 ERK 途径。阐明与这些事件相关的复杂机制可能为揭示 WC-Co 诱导的致癌作用的起始和进展提供新的视角。
