AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-Β-mediated ERK signaling

Department of Surgery, Technische Universität München, Munich, Germany.
Oncogene (Impact Factor: 8.46). 09/2010; 29(37):5146-58. DOI: 10.1038/onc.2010.258
Source: PubMed

ABSTRACT 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.

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Available from: Ivane Abiatari, Apr 09, 2014
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    • "Recently reports showed AZGP1 was overexpressed in some tumors, but lost or reduced in other tumors [13,17]. Although the exact mechanism remains elusive, expression of AZGP1 is partly attributed to the acetylation status of histone which regulates gene activity by changing the conformation of chromatin. "
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    • "Tight junctions are structures between epithelial cells that control movement through the paracellular space and are therefore crucial for the functional epithelial barrier (Steed et al., 2010). The microarray also showed there was significant downregulation of the gene encoding zinc-a2-glycoprotein (Table S1), and silencing of this gene has recently been shown to induce the epithelial-tomesenchymal transition with the concomitant loss of epithelial integrity and downregulation of cell adhesion molecules (Kong et al., 2010). This suggests that colonization results in the downregulation of genes that could directly, or indirectly, result in the opening of the epithelial barrier. "
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