AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-β-mediated ERK signaling
| Autor: | Ivane Abiatari, Irene Esposito, Helmut Friess, Bo Kong, Nataliya Valkovskaya, Simon Rieder, J. Kleeff, Sylvia Streit, Mert Erkan, Xin Hong, Christoph W. Michalski |
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| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
medicine.medical_specialty Tumor suppressor gene Cellular differentiation Vimentin medicine.disease_cause CDH1 Mesoderm Adipokines Transforming Growth Factor beta Cell Line Tumor Internal medicine Genetics medicine Humans Gene silencing Genes Tumor Suppressor Neoplasm Invasiveness Extracellular Signal-Regulated MAP Kinases Molecular Biology Glycoproteins biology Reverse Transcriptase Polymerase Chain Reaction Transdifferentiation Cell Differentiation Epithelial Cells Histone Deacetylase Inhibitors Pancreatic Neoplasms Endocrinology Cell Transdifferentiation biology.protein Cancer research Carrier Proteins Carcinogenesis Signal Transduction |
| Zdroj: | Oncogene. 29:5146-5158 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2010.258 |
| Popis: | Epithelial-to-mesenchymal transdifferentiation (EMT) mediated by transforming growth factor-β (TGF-β) signaling leads to aggressive cancer progression. In this study, we identified zinc-α2-glycoprotein (AZGP1, ZAG) as a tumor suppressor in pancreatic ductal adenocarcinoma whose expression is lost due to histone deacetylation. In vitro, ZAG silencing strikingly increased invasiveness of pancreatic cancer cells accompanied by the induction of a mesenchymal phenotype. Expression analysis of a set of EMT markers showed an increase in the expression of mesenchymal markers (vimentin (VIM) and integrin-α5) and a concomitant reduction in the expression of epithelial markers (cadherin 1 (CDH1), desmoplakin and keratin-19). Blockade of endogenous TGF-β signaling inhibited these morphological changes and the downregulation of CDH1, as elicited by ZAG silencing. In a ZAG-negative cell line, human recombinant ZAG (rZAG) specifically inhibited exogenous TGF-β-mediated tumor cell invasion and VIM expression. Furthermore, rZAG blocked TGF-β-mediated ERK2 phosphorylation. PCR array analysis revealed that ZAG-induced epithelial transdifferentiation was accompanied by a series of concerted cellular events including a shift in the energy metabolism and prosurvival signals. Thus, epigenetically regulated ZAG is a novel tumor suppressor essential for maintaining an epithelial phenotype. |
| Databáze: | OpenAIRE |
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