In vitro and bioinformatics mechanistic-based approach for cadmium carcinogenicity understanding. (June 2020)

• Record Type: Journal Article
• Authors: Oldani, Monica; Fabbri, Marco; Melchioretto, Pasquale; Callegaro, Giulia; Fusi, Paola; Gribaldo, Laura; Forcella, Matilde; Urani, Chiara
• Is Part Of: Toxicology in vitro. Volume 65(2020)
• Publication Date: 2020-06
• Subjects: Cadmium -- Carcinogenesis -- Cell transformation assay -- Toxicogenomics; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2020.104757
• Languages: English
• ISSNs: 0887-2333

Abstract

Abstract: Cadmium is a toxic metal able to enter the cells through channels and transport pathways dedicated to essential ions, leading, among others, to the dysregulation of divalent ions homeostasis. Despite its recognized human carcinogenicity, the mechanisms are still under investigation. A powerful tool for mechanistic studies of carcinogenesis is the Cell Transformation Assay (CTA). We have isolated and characterized by whole genome microarray and bioinformatics analysis of differentially expressed genes (DEGs) cadmium-transformed cells from different foci (F1, F2, and F3) at the end of CTA (6 weeks). The systematic analysis of up- and down-regulated transcripts and the comparison of DEGs in transformed cells evidence different functional targets and the complex picture of cadmium-induced transformation. Only 34 in common DEGs are found in cells from all foci, and among these, only 4 genes are jointly up-regulated ( Ccl2, Ccl5, IL6 and Spp1 ), all responsible for cytokines/chemokines coding. Most in common DEGs are down-regulated, suggesting that the switching-off of specific functions plays a major role in this process. In addition, the comparison of dysregulated pathways immediately after cadmium treatment with those in transformed cells provides a valuable means to the comprehension of the overall process. Highlights: Cell transformation Assay and toxicogenomics are integrated to study cadmium carcinogenesis mechanisms Inflammatory response is the only common feature in Cd-transformed cells from all different foci Switching-off of specific functions plays a major role in Cd-induced carcinogenesis Comparison of triggering signals and deregulated pathways in transformed cells provides hints on cadmium mechanisms