ArticleGastroenterology2015
NFATc1 Links EGFR Signaling to Induction of Sox9 Transcription and Acinar-Ductal Transdifferentiation in the Pancreas.
Article in Gastroenterology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers.
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Who cites it
59 citing papers in PubMed, 101 citations in OpenAlex.
- The effects of telmisartan on the nuclear factor of activated T lymphocytes signalling pathway in hypertensive patients.Journal of the renin-angiotensin-aldosterone system : JRAASTrial
- Acinar-ductal metaplasia in pancreatitis and pancreatic ductal adenocarcinoma.Cellular oncology (Dordrecht, Netherlands) · 2026Review
- The significance of immunogenic cell death related prognostic gene markers in colorectal cancer prognosis and antitumor immunity.Scientific reports · 2026Article
- Role of the SOX family in non‑small cell lung cancer: Molecular mechanisms and therapeutic implications (Review).Oncology reports · 2026Review
- Synergistic roles of NFATc1 and c-Jun in immunomodulation.Biochemistry and biophysics reports · 2025Review
- Therapeutic targeting of FOSL1 and RELA-dependent transcriptional mechanisms to suppress pancreatic cancer metastasis.Cell death & disease · 2025Article
- Drug-induced pancreatitis: a real-world analysis of the FDA Adverse Event Reporting System and network pharmacology.Frontiers in pharmacology · 2025Article
- TRIM-endous functional network of tripartite motif 29 (TRIM29) in cancer progression and beyond.Cancer metastasis reviews · 2024Review
- Epigenetic control ofHeliyon · 2024Article
- DTX3L Accelerates Pancreatic cancer Progression via FAK/PI3K/AKT Axis.Biochemical genetics · 2024Article
- Deubiquitinase PSMD7 facilitates pancreatic cancer progression through activating Nocth1 pathway via modifying SOX2 degradation.Cell & bioscience · 2024Article
- Subtype Transdifferentiation in Human Cancer: The Power of Tissue Plasticity in Tumor Progression.Cells · 2024Review
- Macrophage-induced reactive oxygen species in the initiation of pancreatic cancer: a mini-review.Frontiers in immunology · 2024Review
- ST6GAL1 sialyltransferase promotes acinar to ductal metaplasia and pancreatic cancer progression.JCI insight · 2023Article
- Acinar-to-Ductal Metaplasia (ADM): On the Road to Pancreatic Intraepithelial Neoplasia (PanIN) and Pancreatic Cancer.International journal of molecular sciences · 2023Review
- Muc4 loss mitigates epidermal growth factor receptor activity essential for PDAC tumorigenesis.Oncogene · 2023Article
- Review
- Article
- Article
- Molecular signaling in pancreatic ductal metaplasia: emerging biomarkers for detection and intervention of early pancreatic cancer.Cellular oncology (Dordrecht, Netherlands) · 2022Review
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Authors and funding
15 authors at 7 institutions in 3 countries.
Funding
Abstract
BACKGROUND &
aimsOncogenic mutations in KRAS contribute to the development of pancreatic ductal adenocarcinoma, but are not sufficient to initiate carcinogenesis. Secondary events, such as inflammation-induced signaling via the epidermal growth factor receptor (EGFR) and expression of the SOX9 gene, are required for tumor formation. Herein we sought to identify the mechanisms that link EGFR signaling with activation of SOX9 during acinar-ductal metaplasia, a transdifferentiation process that precedes pancreatic carcinogenesis.
methodsWe analyzed pancreatic tissues from Kras(G12D);pdx1-Cre and Kras(G12D);NFATc1(Δ/Δ);pdx1-Cre mice after intraperitoneal administration of caerulein, vs cyclosporin A or dimethyl sulfoxide (controls). Induction of EGFR signaling and its effects on the expression of Nuclear factor of activated T cells c1 (NFATc1) or SOX9 were investigated by quantitative reverse-transcription polymerase chain reaction, immunoblot, and immunohistochemical analyses of mouse and human tissues and acinar cell explants. Interactions between NFATc1 and partner proteins and effects on DNA binding or chromatin modifications were studied using co-immunoprecipitation and chromatin immunoprecipitation assays in acinar cell explants and mouse tissue.
resultsEGFR activation induced expression of NFATc1 in metaplastic areas from patients with chronic pancreatitis and in pancreatic tissue from Kras(G12D) mice. EGFR signaling also promoted formation of a complex between NFATc1 and C-JUN in dedifferentiating mouse acinar cells, leading to activation of Sox9 transcription and induction of acinar-ductal metaplasia. Pharmacologic inhibition of NFATc1 or disruption of the Nfatc1 gene inhibited EGFR-mediated induction of Sox9 transcription and blocked acinar-ductal transdifferentiation and pancreatic cancer initiation in mice.
conclusionsEGFR signaling induces expression of NFATc1 and Sox9, leading to acinar cell transdifferentiation and initiation of pancreatic cancer. Strategies designed to disrupt this pathway might be developed to prevent pancreatic cancer initiation in high-risk patients with chronic pancreatitis.
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