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

Kong B., Michalski C. W., Hong X., Valkovskaya N., Rieder S., Abiatari I., ...Daha Fazla

ONCOGENE, cilt.29, sa.37, ss.5146-5158, 2010 (SCI-Expanded) identifier identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 29 Sayı: 37
  • Basım Tarihi: 2010
  • Doi Numarası: 10.1038/onc.2010.258
  • Dergi Adı: ONCOGENE
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.5146-5158
  • Acıbadem Mehmet Ali Aydınlar Üniversitesi Adresli: Hayır

Özet

Epithelial-to-mesenchymal transdifferentiation (EMT) mediated by transforming growth factor-beta (TGF-beta) signaling leads to aggressive cancer progression. In this study, we identified zinc-alpha 2-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-alpha 5) and a concomitant reduction in the expression of epithelial markers (cadherin 1 (CDH1), desmoplakin and keratin-19). Blockade of endogenous TGF-beta 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-beta-mediated tumor cell invasion and VIM expression. Furthermore, rZAG blocked TGF-beta-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. Oncogene (2010) 29, 5146-5158; doi:10.1038/onc.2010.258; published online 28 June 2010