2219 9 9652 1 26797 document 9652 AZGP1 is a tumor suppressor in pancreatic cancer.pdf application/pdf 0fd8383db74d5556e7a6d48b42d11f0f MD5 1325981 2015-04-29 13:44:42 http://eprints.iliauni.edu.ge/2219/1/AZGP1%20is%20a%20tumor%20suppressor%20in%20pancreatic%20cancer.pdf 2219 1 1 application/pdf text en public
AZGP1 is a tumor suppressor in pancreatic cancer.pdf
 archive 207 disk0/00/00/22/19 2015-04-30 05:25:21 2015-04-30 05:25:21 2015-04-30 05:25:21 article show Kong B Michalski C W Hong X Valkovskaya N Rieder S Abiatari Ivane ivane.abiatari@iliauni.edu.ge Streit S Erkan M Esposito I Friess H Kleeff J AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-β-mediated ERK signaling. pub RC0254 public 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. 2010-09-16 published Oncogene 29 37 5146-58 TRUE 1476-5594