title: AGR2 is a SMAD4-suppressible gene that modulates MUC1 levels and promotes the initiation and progression of pancreatic intraepithelial neoplasia.
abstract: The mechanisms controlling expression of the putative oncogene Anterior gradient 2 (AGR2) in pancreatic ductal adenocarcinoma (PDAC) are not well understood. We now show that AGR2 is a transforming growth factor-β (TGF-β)-responsive gene in human pancreatic cancer cells, whose downregulation is SMAD4 dependent. We also provide evidence supporting a role for AGR2 as an ER-chaperone for the cancer-associated mucin, MUC1. AGR2 is both sufficient and required for MUC1 expression in pancreatic cancer cells. Furthermore, AGR2 is coexpressed with MUC1 in mouse pancreatic intraepithelial neoplasia (mPanIN)-like lesions and in the cancer cells of four distinct genetically engineered mouse models of PDAC. We also show that Pdx1-Cre/LSL-Kras(G12D)/Smad4(lox/lox) mice heterozygous for Agr2 exhibit a delay in mPanIN initiation and progression to PDAC. It is proposed that loss of Smad4 may convert TGF-β from a tumor suppressor to a tumor promoter by causing the upregulation of AGR2, which then leads to increased MUC1 expression, at which point both AGR2 and MUC1 facilitate mPanIN initiation and progression to PDAC.
authors.affiliation: Department of Medicine, Dartmouth Medical School, Hanover, NH, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Norris
authors.forename: A
authors.initials: A
authors.lastname: Gore
authors.forename: A
authors.initials: A
authors.lastname: Balboni
authors.forename: A
authors.initials: A
authors.lastname: Young
authors.forename: D S
authors.initials: DS
authors.lastname: Longnecker
authors.forename: M
authors.initials: M
authors.lastname: Korc
mesh_terms: D000818:Animals; D002278:Carcinoma in Situ / Q000235:genetics / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D018396:Mucin-1 / Q000096:biosynthesis*; D009088:Mucoproteins; D015513:Oncogene Proteins; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D051901:Smad4 Protein / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome; D014162:Transfection
chemical_list: C502296:AGR2 protein, human; D018396:Mucin-1; D009088:Mucoproteins; D015513:Oncogene Proteins; D011506:Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein