FRA1对于维持体外长期砷暴露诱导的致癌表型至关重要

IF 2.9 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY Metallomics Pub Date : 2020-11-20 DOI:10.1039/D0MT00209G
Irene Barguilla, Jordi Bach, Jana Peremartí, Ricard Marcos and Alba Hernández
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引用次数: 3

摘要

砷诱导致癌效应,激活与应激相关的信号通路。这可能导致AP-1蛋白,特别是其FRA1成分的过度激活。FRA1是上皮肿瘤中经常过表达的转录因子,可调控不同靶基因的表达。因此,FRA1可能在砷诱导的体外细胞转化中发挥重要作用。在长期暴露于2 μM砷的40周内,监测MEF细胞在整个转化阶段的FRA1水平。有趣的是,结果显示随着时间的推移,FRA1逐渐过表达(mRNA和pFRA/non-pFRA1在第40周分别为60倍和11倍),这可能是导致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mapk (ERK、p38和JNK)和FRA1上游的其他已知参与者的水平,并确定了ERK、p38和RAS作为参与砷诱导的FRA1激活的潜在候选人。此外,在慢性砷暴露环境下,FRA1的稳定敲低会对细胞的致癌表型相关特征产生显著影响。值得注意的是,FRA1敲除细胞的增殖率降低30%,迁移和侵袭潜力降低50%,衰老减少50%,肿瘤球形成能力降低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。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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FRA1 is essential for the maintenance of the oncogenic phenotype induced by in vitro long-term arsenic exposure†

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.

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来源期刊
Metallomics
Metallomics 生物-生化与分子生物学
CiteScore
7.00
自引率
5.90%
发文量
87
审稿时长
1 months
期刊介绍: Global approaches to metals in the biosciences
期刊最新文献
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