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

Oncogene volume 29, pages 5146–5158 (2010)Cite this article

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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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Acknowledgements

We thank Felicitas Altmayr, Tanja Rossmann-Bloeck, Manja Thorwirth and Carmen Marthen for excellent technical support. This study was in part supported by the European Union (within the framework of the ‘MolDiagPaca’ project; to JK, CWM and HF) and by the commission for clinical research of the TU Munich (KKF). BK received a fellowship from the Scholarship Council of the Ministry of Education of China.

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  1. B Kong and C W Michalski: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery, Technische Universität München, Munich, Germany

    B Kong, C W Michalski, X Hong, N Valkovskaya, S Rieder, I Abiatari, S Streit, M Erkan, H Friess & J Kleeff

  2. Institute of Pathology, Technische Universität München, Munich, Germany

    I Esposito

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Kong, B., Michalski, C., Hong, X. et al. AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-β-mediated ERK signaling. Oncogene 29, 5146–5158 (2010). https://doi.org/10.1038/onc.2010.258

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