Title: Impact of cadmium on intracellular zinc levels in HepG2 cells: quantitative evaluations and molecular effects
Authors: URANI ChiaraMELCHIORETTO PasqualeBRUSCHI MaurizioFABBRI MarcoSACCO Maria-GraziaGRIBALDO Laura
Citation: BIOMED RESEARCH INTERNATIONAL vol. 2015 p. 949514
Publication Year: 2015
JRC N°: JRC93413
ISSN: 2314-6133
URI: http://www.hindawi.com/journals/bmri/2015/949514/
DOI: 10.1155/2015/949514
Type: Articles in periodicals and books
Abstract: Cadmium is ranked as one of the top ten hazardous substances and classified as a probable human carcinogen. Due to its molecular mimicry, cadmium follows a Trojan horse strategy leading to interference with essential metals homeostasis. Cadmium toxicity has been closely related to zinc homeostasis. However, even though the disturbance of cadmium in zinc homeostasis has already been recognized, as probably due to the displacement of zinc from native proteomic binding sites, its extent, as well as molecular mechanisms involved in cadmium carcinogenesis have still to be fully clarified. To this end, we used the zinc-specific fluorescent probe Zinquin to visualize by microscopy, and to quantitatively evaluate by spectrofluorimetry, changes in the concentration of labile zinc in an in vitro model of human hepatic cells (HepG2) exposed to cadmium. A very large increase (+93% versus basal fluorescence intensities) of intracellular labile zinc was measured when HepG2 cells were exposed to 10 µM cadmium for 24 hrs. The zinc-related fluorescence was predominantly distributed in the cytoplasm and in the perinuclear region, and had a punctate appearance. Microarray expression profiling showed that in the HepG2 cells, featuring an increase of labile zinc after cadmium exposure, one of the top regulated genes is Snail1 (+3.6 fold change), which is included, among others, in the adherens junction pathway and linked to cancer. Other regulated genes in the same pathway are MET (+1.4), TGF-R (+1.0), and two members of the Rho-family GTPase, Rac (+1.5) and cdc42 (+1.5), all implicated in the loss of adherence features, and acquisition of migratory and cancer properties. In addition, the microRNAs analysis showed a down-regulation of miR-34a (-1.1) and miR-200a (-1.2), both implicated in the epithelial-mesenchymal transition. These microRNAs results further support the role played by zinc in affecting gene expression at the post-transcriptional level.
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