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

Oncogene volume 32, pages 3867–3876 (2013)Cite this article

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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-KrasG12D/Smad4lox/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.

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Acknowledgements

We thank Dr Ted R Hupp (U of Edinburgh) for the AGR2-RFP and pcDNA-AGR2 plasmids; Dr Park (UCSF) for providing the Agr2−/− mice; Dr J Gore for helpful discussions; and Ms Catherine Chen for excellent laboratory work. This research was supported by the US Public Health Service Grant CA-R37-075059, awarded by the National Cancer Institute to MK. AMN was supported by the NRSA Molecular and Toxicology Program fellowship 5T32CA009658-18. AB was supported by the Program in Experimental and Molecular Medicine.

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Authors and Affiliations

  1. Department of Medicine, Dartmouth Medical School, Hanover, NH, USA

    A M Norris & A Young

  2. Departments of Medicine, Biochemistry and Molecular Biology, Indiana University School of Medicine, the Melvin and Bren Simon Cancer Center, and the Pancreatic Cancer Signature Center, Indianapolis, IN, USA

    A Gore & M Korc

  3. Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH, USA

    A Balboni

  4. Department of Pathology, Dartmouth Medical School, Hanover, NH, USA

    D S Longnecker

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  1. A M Norris
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Correspondence to M Korc.

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Norris, A., Gore, A., Balboni, A. et al. AGR2 is a SMAD4-suppressible gene that modulates MUC1 levels and promotes the initiation and progression of pancreatic intraepithelial neoplasia. Oncogene 32, 3867–3876 (2013). https://doi.org/10.1038/onc.2012.394

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