RRC ID 67293
Author Mizuuchi Y, Aishima S, Ohuchida K, Shindo K, Fujino M, Hattori M, Miyazaki T, Mizumoto K, Tanaka M, Oda Y.
Title Anterior gradient 2 downregulation in a subset of pancreatic ductal adenocarcinoma is a prognostic factor indicative of epithelial-mesenchymal transition.
Journal Lab Invest
Abstract Anterior gradient 2 (AGR2), a member of the protein disulfide isomerase family, has been implicated in various cancers including pancreatic ductal adenocarcinoma (PDAC) and is known to promote cancer progression. However, the prognostic value of AGR2 expression and the interaction with epithelial-mesenchymal transition (EMT) remain unclear. We investigated the clinical significance of AGR2 and EMT markers in PDAC patients by immunohistochemical analyses. Although AGR2 expression was not observed in normal pancreas, all pancreatic precursor neoplastic lesions were positive for AGR2, even at the earliest stages, including pancreatic intraepithelial neoplasia-1A, AGR2 expression was reduced in 27.7% (54/195 cases) of PDAC patients. AGR2 downregulation correlated with EMT markers (vimentin overexpression and reduced membranous E-cadherin expression), high Union for International Cancer Control stage (P<0.0001), high histological cellular grade (P<0.0001), and adverse outcome (P<0.0001). In vitro, targeted silencing of AGR2 in cancer cells using siRNA reduced cell proliferation, colony formation, cell invasiveness, and migration, but did not alter EMT markers. To confer a more aggressive phenotype and induce EMT in PDAC cells, we co-cultured PDAC cell lines with primary-cultured pancreatic stellate cells (PSCs) and found that AGR2 was downregulated in co-cultured PDAC cells compared with PDAC monocultures. Treatment with transforming growth factor beta-1 (TGF-β), secreted from PSCs, decreased AGR2 expression, whereas inhibition of TGF-β signaling using recombinant soluble human TGF-β receptor type II and TGF-β-neutralizing antibodies restored AGR2 expression. We conclude that AGR2 downregulation is a useful prognostic marker, induced by EMT, and that secreted TGF-β from PSCs may partially contribute to AGR2 downregulation in PDAC patients. AGR2 downregulation does not induce EMT or a more aggressive phenotype, but is a secondary effect of these processes in advanced PDAC.
Volume 95(2)
Pages 193-206
Published 2015-2-1
DOI 10.1038/labinvest.2014.138
PII labinvest2014138
PMID 25418581
MeSH Biomarkers, Tumor / metabolism* Blotting, Western Cadherins / metabolism Carcinoma, Pancreatic Ductal / metabolism* Cell Movement / physiology Cell Proliferation / physiology Colony-Forming Units Assay DNA Primers / genetics Enzyme-Linked Immunosorbent Assay Epithelial-Mesenchymal Transition / genetics Epithelial-Mesenchymal Transition / physiology* Gene Expression Regulation, Neoplastic / drug effects Gene Expression Regulation, Neoplastic / physiology* Humans Immunohistochemistry Infectious pancreatic necrosis virus / metabolism* Kaplan-Meier Estimate Mucoproteins Neoplasm Invasiveness / physiopathology Oncogene Proteins Prognosis Proteins / metabolism* RNA Interference Real-Time Polymerase Chain Reaction Transforming Growth Factor beta / antagonists & inhibitors Transforming Growth Factor beta / pharmacology Vimentin / metabolism
IF 4.197
Human and Animal Cells PANC-1(RCB2095)