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: 8.56). 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.

Download full-text


Available from: Ivane Abiatari, Apr 09, 2014
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Streptococcus pneumoniae and Haemophilus influenzae are members of the normal human nasal microbiota with the ability to cause invasive infections. Bacterial invasion requires translocation across the epithelium; however, mechanistic understanding of this process is limited. Examining the epithelial response to murine colonization by S. pneumoniae and H. influenzae, we observed the TLR-dependent downregulation of claudins 7 and 10, tight junction components key to the maintenance of epithelial barrier integrity. When modeled in vitro, claudin downregulation was preceded by upregulation of SNAIL1, a transcriptional repressor of tight junction components, and these phenomena required p38 MAPK and TGF-β signaling. Consequently, downregulation of SNAIL1 expression inhibited bacterial translocation across the epithelium. Furthermore, disruption of epithelial barrier integrity by claudin 7 inhibition in vitro or TLR stimulation in vivo promoted bacterial translocation. These data support a general mechanism for epithelial opening exploited by invasive pathogens to facilitate movement across the epithelium to initiate disease.
    Cell host & microbe 05/2011; 9(5):404-14. DOI:10.1016/j.chom.2011.04.012 · 12.19 Impact Factor
  • Source
    Journal of gastrointestinal oncology 09/2010; 1(1):24-33. DOI:10.3978/j.issn.2078-6891.2010.009
  • [Show abstract] [Hide abstract]
    ABSTRACT: Epithelial-mesenchymal transition (EMT) is initially considered as a physiological phenomenon during the embryogenesis of mammals, as well as a basic biological event maintaining the stability of the vital body. Recent researches indicated that EMT plays a critical role in various tumors progression, through which epithelial cancers invade and metastasize. The cell characteristics are changed during EMT, in which the cells lose cell-cell and cell-matrix interactions and apical polarity, reorganize their cytoskeleton, and become isolated, motile, as well as resistant to anoikis, then become spindle-shaped mesenchymal cells. This review lays emphasis on studying the cell morphogenesis, makers and molecular mechanism regulation about EMT, discussing the relationship between the EMT and the cancer development and metastasis. Key wordsEMT–molecular mechanism–cancer–metastasis
    The Chinese-German Journal of Clinical Oncology 03/2011; 10(3):125-133. DOI:10.1007/s10330-011-0740-8