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Cited by 79Pancreatic and Hepatic Oncology ResearchTGF-β signaling in diseasesCholangiocarcinoma and Gallbladder Cancer Studies

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

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Norris, A M, Gore, A, Balboni, A, Young, A, Longnecker, D S, Korc, M·2013·Oncogene
DOI 10.1038/onc.2012.394PMC PMC3515713
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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-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.

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  • AGR2 is essential for MUC1 expression, interacts with MUC1 in the endoplasmic reticulum, and its deficiency leads to reduced MUC1 expression in pancreatic lesions.

    “AGR2, essential for MUC1 expression, interacts with MUC1 in the endoplasmic reticulum (ER), and its deficiency leads to reduced MUC1 expression in pancreatic lesions [116,117].”

    From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [117]

    The Results report that AGR2 knockdown reduces MUC1 protein in pancreatic cancer cells; the Discussion reports parallel reductions in pancreatic lesions with low or absent AGR2. Co-localization and co-immunoprecipitation suggest an interaction, and AGR2 is shown to localize mostly to the ER, but the paper does not establish that the AGR2–MUC1 interaction occurs specifically in the ER. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • TGF-β1 down-regulated AGR2 in pancreatic cancer cell lines, and SMAD4 was identified as a key mediator in this regulation.

    “TGF-β1 down-regulated AGR2 in pancreatic cancer cell lines, and SMAD4 was identified as a key mediator in this regulation.”

    From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [117]

  • Knocking down SMAD4 in pancreatic cancer cells leads to increased radio-resistance, heightened DNA damage, genomic instability and decreased levels of key DNA double-strand break repair proteins.

    “Knocking down SMAD4 in pancreatic cancer cells leads to increased radio-resistance, heightened DNA damage, genomic instability and decreased levels of key DNA double-strand break repair proteins [64,117].”

    From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [117]

    The Results section (‘AGR2 expression is regulated by SMAD4’; page not supplied) reports that SMAD4 knockdown increased AGR2 levels in pancreatic cancer cells. The Discussion likewise concerns AGR2 regulation, not radio-resistance, DNA damage, genomic instability, or double-strand break repair proteins. Searches for radiation resistance and DNA-repair outcomes found no passage addressing the claimed effects. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • SMAD4 depletion induces resistance to ionizing radiation.

    “Additionally, a study exploring SMAD4 gene mutation’s impact on pancreatic cancer response to radiotherapy reveals that SMAD4 depletion induces resistance to ionizing radiation.”

    From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [117]

    The Results section reports that SMAD4 knockdown increased AGR2 levels, while the Introduction discusses resistance to TGF-β-mediated growth inhibition—not radiation. Searches for ionizing radiation, radiotherapy, irradiation, and radiosensitivity found no passage in our copy addressing whether SMAD4 depletion affects radiation resistance. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Cited by

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Authors
Norris, A. M., Gore, A., Balboni, A., Young, A., Longnecker, D. S., & Korc, M.
Affiliations
  • Dartmouth College (US)
  • Indiana University Indianapolis (US)
Corresponding author
Korc, M
ORCID
Venue
Oncogene
Publisher
Springer Science and Business Media LLC
Published
2012-09-03
Volume
32
Issue
33
Pages
3867-3876
ISSN
  • 0950-9232 (ISSN-L)
  • 1476-5594
DOI
10.1038/onc.2012.394
PMC
PMC3515713
OpenAlex
W2081341738
Cited by
79
References
2
Citations by year
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FWCI
3.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Oncogene (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion)
Funders
  • U.S. Public Health Service
  • University of California, San Francisco
  • National Cancer Institute (R01CA075059, R37CA075059, CA-R37-075059, T32CA009658)
Topics
  • Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Health Sciences › Medicine › Surgery › Cholangiocarcinoma and Gallbladder Cancer Studies
Keywords
AGR2, SMAD4, MUC1, pancreatic intraepithelial neoplasia, pancreatic ductal adenocarcinoma, TGF-beta signaling, ER chaperones, oncogenic transformation
MeSH terms
Animals, Carcinoma in Situ, Cell Transformation, Neoplastic, Humans, Immunohistochemistry, Mucoproteins, Pancreatic Neoplasms, Proteins, Transfection, Immunoblotting, Oncogene Proteins, Gene Expression Regulation, Neoplastic, Mucin-1, Disease Progression, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, Immunoprecipitation, Mice, Smad4 Protein, Transcriptome

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