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

Abstract

Epithelial-to-mesenchymal transdifferentiation (EMT) mediated by transforming growth factor-b (TGF-b) signaling leads to aggressive cancer progression. In this study, we identified zinc-a2-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-a5) and a concomitant reduction in the expression of epithelial markers (cadherin 1 (CDH1), desmoplakin and keratin-19). Blockade of endogenous TGF-b 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-b-mediated tumor cell invasion and VIM expression. Furthermore, rZAG blocked TGF-b-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.

Zinc-α2-Glycoprotein Exerts Antifibrotic Effects in Kidney and Heart

“…Instead, we found that AZGP1 attenuated TGFb-induced canonical Smad2 and Smad3 signaling. AZGP1 also inhibited TGF-b noncanonical ERK phosphorylation, mirroring findings by Kong et al 24 Additionally, we observed that blockade of AZGP1 internalization by genistein or caveolin-1 knockdown resulted in a significant reduction of TGF-b inhibition. Additional studies will be necessary to elucidate the underlying mechanisms that regulate this interplay.…”

“…26 Enhanced tumor progression has been shown to correlate with lower expression of epithelial AZGP1. [20][21][22][23] Kong et al 24 found that AZGP1 expression can preserve epithelial integrity by promoting mesenchymal-toepithelial transition in pancreatic cancer cells. Kong et al 24 attributed the prodifferentiation effects of AZGP1 to TGF-b antagonistic properties.…”

“…[20][21][22][23] Along these lines, AZGP1 was linked to inhibition of TGFb-mediated dedifferentiation in pancreatic cancer cells. 24 On the basis of these data, we tested the hypothesis that AZGP1 negatively regulates the development of organ fibrosis.…”

Metabolism gene signatures and surgical site infections in abdominal surgery

“…AZGP1 staining was observed in a majority of adipocytes, consistent with its molecular identity as an adipokine (Fig. 1A, lower panel) [26,27]. In contrast, immunoreactivity of ALDH1A3 could be detected in cells within vascular structures (Fig 1C, lower panel).…”

A signature for immune response correlates with HCV treatment outcome in Caucasian subjects

“…CNDP1, a histidine dipeptidase, was expressed at lower levels in individuals with more severe fibrosis [36]. AZGP1 was reported to be a tumor suppressor in pancreatic cancer [37]. Low expression of AZGP1 predicted recurrence in prostate cancer [38] and is associated with poor prognosis in liver cancer [39].…”