AGR2 is a SMAD4-suppressible gene that modulates MUC1 levels and promotes the initiation and progression of pancreatic intraepithelial neoplasia

A. M. Norris, A. Gore, A. Balboni, A. Young, D. S. Longnecker, M. Korc

Research output: Contribution to journalArticle

30 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3867-3876
Number of pages10
JournalOncogene
Volume32
Issue number33
DOIs
StatePublished - Aug 15 2013

Keywords

  • AGR2
  • MUC1
  • pancreatic cancer
  • SMAD4
  • TGF-β

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

AGR2 is a SMAD4-suppressible gene that modulates MUC1 levels and promotes the initiation and progression of pancreatic intraepithelial neoplasia. / Norris, A. M.; Gore, A.; Balboni, A.; Young, A.; Longnecker, D. S.; Korc, M.

In: Oncogene, Vol. 32, No. 33, 15.08.2013, p. 3867-3876.

Research output: Contribution to journalArticle