Group of Mutagenesis, Department of Genetics and Microbiology, Faculty of Biosciences, Universitat Autònoma de Barcelona, Edifici Cn, Campus de Bellaterra, 08193 Cerdanyola del Vallès (Barcelona), Spain.
Metallomics. 2020 Dec 23;12(12):2161-2173. doi: 10.1039/d0mt00209g.
Arsenic induces oncogenic effects activating stress-related signalling pathways. This can result in the over-activation of the AP-1 protein, specifically its FRA1 component. FRA1 is a transcription factor frequently overexpressed in epithelial tumors, where it can regulate the expression of different target genes. Accordingly, FRA1 could play an essential role in the in vitro cell transformation induced by arsenic. FRA1 levels were monitored in MEF cells throughout their transformation stages during 40 weeks of long-term 2 μM arsenic exposure. Interestingly, the results show a progressive FRA1 overexpression with time (60-fold and 11-fold for mRNA and pFRA/non-pFRA1, respectively, at week 40), which may be responsible for the observed altered expression in the FRA1 downstream target genes Pten, Pdcd4, Tpm1, Tgfb1, Tgfb2, Zeb1, Zeb2, and Twist. The levels of MAPKs (ERK, p38, and JNK) and other known players upstream from FRA1 were assessed at equivalent time-points, and ERK, p38 and RAS were pinpointed as potential candidates involved in arsenic-induced FRA1 activation. Furthermore, FRA1 stable knockdown under chronic arsenic exposure settings elicits a remarkable impact on the features relative to the cells' oncogenic phenotype. Notably, FRA1 knockdown cells present a 30% diminished proliferation rate, a 50% lowered migration and invasion potential, a 50% reduction in senescence, and a 30-60% reduced tumorsphere-forming ability. This work is the first to demonstrate the important role of FRA1 in the development and aggressiveness of the in vitro transformed phenotype induced by long-term arsenic exposure.
砷诱导致癌作用，激活应激相关信号通路。这可能导致 AP-1 蛋白的过度激活，特别是其 FRA1 成分。FRA1 是上皮肿瘤中经常过表达的转录因子，它可以调节不同靶基因的表达。因此，FRA1 可能在砷诱导的体外细胞转化中发挥重要作用。在长期 2 μM 砷暴露的 40 周内，监测 MEF 细胞在其转化阶段的 FRA1 水平。有趣的是，结果显示随着时间的推移 FRA1 表达逐渐增加（mRNA 和 pFRA/non-pFRA1 分别增加 60 倍和 11 倍，在第 40 周），这可能是观察到 FRA1 下游靶基因 Pten、Pdcd4、Tpm1、Tgfb1、Tgfb2、Zeb1、Zeb2 和 Twist 表达改变的原因。在等效时间点评估了 MAPKs（ERK、p38 和 JNK）和 FRA1 上游的其他已知参与者的水平，并且确定 ERK、p38 和 RAS 是参与砷诱导 FRA1 激活的潜在候选者。此外，在慢性砷暴露环境下稳定敲低 FRA1 会对细胞致癌表型的特征产生显著影响。值得注意的是，FRA1 敲低细胞的增殖率降低了 30%，迁移和侵袭潜力降低了 50%，衰老减少了 50%，肿瘤球形成能力降低了 30-60%。这项工作首次证明了 FRA1 在长期砷暴露诱导的体外转化表型的发展和侵袭性中的重要作用。
