Title: Cadmium exposure upregulates SNAIL through miR-30 repression in human lung epithelial cells.
Authors: Tanwar, Vinay Singh; Zhang, Xiaoru; Jagannathan, Lakshmanan; Jose, Cynthia C; Cuddapah, Suresh
Published In Toxicol Appl Pharmacol, (2019 06 15)
Abstract: Cadmium (Cd) is a known human lung carcinogen. In addition, Cd exposure is associated with several lung diseases including emphysema, chronic obstructive pulmonary disease (COPD), asthma and fibrosis. Although earlier studies have identified several processes dysregulated by Cd exposure, the underlying mechanisms remain unclear. Here, we examined the transcriptome of lung epithelial cells exposed to Cd to understand the molecular basis of Cd-induced diseases. Computational analysis of the transcriptome predicted a significant number of Cd-upregulated genes to be targets of miR-30 family miRNAs. Experimental validation showed downregulation of all the miR-30 family members in Cd exposed cells. We found SNAIL, an EMT master regulator, to be the most upregulated among the miR-30 targets. Furthermore, we found decrease in the levels of epithelial marker E- cadherin (CDH1) and increase in the levels of mesenchymal markers, ZEB1 and vimentin. This suggested induction of EMT in Cd exposed cells. Luciferase reporter assays showed that miR-30 repressed SNAIL by directly targeting its 3' UTR. Over expression of miR-30e and transfection of miR-30e mimics reduced Cd-induced SNAIL upregulation. Our results suggest that miR-30 negatively regulates SNAIL in lung epithelial cells and that Cd-induced downregulation of miR-30 relieves this repression, resulting in SNAIL upregulation and EMT induction. EMT plays a major role in many diseases associated with Cd exposure including fibrosis, COPD, and cancer and metastasis. Therefore, our identification of miR-30 downregulation in Cd exposed cells and the consequent activation of SNAIL provides important mechanistic insights into lung diseases associated with Cd exposure.
PubMed ID: 30998937
MeSH Terms: 3' Untranslated Regions; Antigens, CD/genetics; Antigens, CD/metabolism; Binding Sites; Cadherins/genetics; Cadherins/metabolism; Cadmium Chloride/toxicity*; Cell Line; Down-Regulation; Epithelial Cells/drug effects*; Epithelial Cells/metabolism; Epithelial Cells/pathology; Epithelial-Mesenchymal Transition/drug effects; Humans; Lung/drug effects*; Lung/metabolism; Lung/pathology; MicroRNAs/genetics; MicroRNAs/metabolism*; Signal Transduction; Snail Family Transcription Factors/genetics; Snail Family Transcription Factors/metabolism*; Transcriptome; Up-Regulation; Vimentin/genetics; Vimentin/metabolism; Zinc Finger E-box-Binding Homeobox 1/genetics; Zinc Finger E-box-Binding Homeobox 1/metabolism