AZGP1 is a tumor suppressor in pancreatic cancer inducing mesenchymal-to-epithelial transdifferentiation by inhibiting TGF-β-mediated ERK signaling.
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.
Kong
B
B
Department of Surgery, Technische Universität München, Munich, Germany.
Michalski
C W
CW
Hong
X
X
Valkovskaya
N
N
Rieder
S
S
Abiatari
I
I
Streit
S
S
Erkan
M
M
Esposito
I
I
Friess
H
H
Kleeff
J
J
D054392:Adipokines; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D054338:Cell Transdifferentiation; D004847:Epithelial Cells / Q000473:pathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D006023:Glycoproteins / Q000235:genetics / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D008648:Mesoderm / Q000473:pathology*; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000473:pathology* / Q000503:physiopathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000502:physiology*; D000090203:Zn-Alpha-2-Glycoprotein
D054392:Adipokines; D002352:Carrier Proteins; D048049:Extracellular Signal-Regulated MAP Kinases; D006023:Glycoproteins; D056572:Histone Deacetylase Inhibitors; D016212:Transforming Growth Factor beta; C488891:AZGP1 protein, human; D000090203:Zn-Alpha-2-Glycoprotein