ArticleBMC cancer2016
The anti-oxidative transcription factor Nuclear factor E2 related factor-2 (Nrf2) counteracts TGF-β1 mediated growth inhibition of pancreatic ductal epithelial cells -Nrf2 as determinant of pro-tumorigenic functions of TGF-β1.
Article in BMC cancer, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers, 1 of them a synthesis that pooled it.
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Who cites it
12 citing papers in PubMed, 1 synthesis or guideline pooled it, 19 citations in OpenAlex.
- Dual roles and therapeutic potential of Keap1-Nrf2 pathway in pancreatic cancer: a systematic review.Cell communication and signaling : CCS · 2019Pooled it
- Selective targeting of genes regulated by zinc finger proteins in endometriosis and endometrioid adenocarcinoma by zinc niflumato complex with neocuproine.Scientific reports · 2025Article
- The Role of Nrf2 in the Regulation of Mitochondrial Function and Ferroptosis in Pancreatic Cancer.Antioxidants (Basel, Switzerland) · 2024Review
- Role of Nrf2 in Pancreatic Cancer.Antioxidants (Basel, Switzerland) · 2021Review
- The Interplay between Oxidative Stress, Inflammation and Angiogenesis in Bladder Cancer Development.International journal of molecular sciences · 2021Review
- NRF2 Knockdown Resensitizes 5-Fluorouracil-Resistant Pancreatic Cancer Cells by Suppressing HO-1 and ABCG2 Expression.International journal of molecular sciences · 2020Article
- Review
- Article
- Expression of Keap1 and Nrf2 in diffuse large B-cell lymphoma and its clinical significance.Experimental and therapeutic medicine · 2018Article
- Isoliquiritigenin Protects Against Pancreatic Injury and Intestinal Dysfunction After Severe Acute Pancreatitis via Nrf2 Signaling.Frontiers in pharmacology · 2018Article
- Immunological Approaches Towards Cancer and Inflammation: A Cross Talk.Frontiers in immunology · 2018Review
- Dichotomous roles of TGF-β in human cancer.Biochemical Society transactions · 2016Review
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundNuclear factor E2 related factor-2 (Nrf2) is an oxidative stress inducible transcription factor being essential in regulating cell homeostasis. Thus, acute induction of Nrf2 in epithelial cells exposed to inflammation confers protection from oxidative cell damage and mutagenesis supporting an anti-tumorigenic role for Nrf2. However, pancreatic ductal adenocarcinoma (PDAC) is characterized by persistent Nrf2 activity conferring therapy resistance which points to a pro-tumorigenic role of Nrf2. A similar dichotomous role in tumorigenesis is described for the Transforming Growth Factor-beta 1 (TGF-β1). The present study therefore aimed at elucidating whether the switch of Nrf2 function towards a tumor promoting one relates to the modulation of TGF-β1 induced cell responses and whether this might occur early in PDAC development.
methodsIn situ analysis comprised immunohistochemical stainings of activated (phosphorylated) Nrf2 and Ki67 in pancreatic tissues containing normal ducts and pancreatic intraepithelial neoplasia (PanINs). In vitro, Nrf2 levels in benign (H6c7-pBp), premalignant (H6c7-kras) and malignant (Colo357) pancreatic ductal epithelial cells were modulated by Nrf2 specific siRNA or Nrf2 overexpression. Then, the effect of Nrf2 alone and in combination with TGF-β1 on cell growth and survival was investigated by cell counting, Ki67 staining and apoptosis assays. The underlying cell signaling was investigated by western blotting. Statistical analysis was performed by Shapiro-Wilk test for normal distribution. Parametric data were analyzed by one-way ANOVA, while non-parametric data were analyzed by Kruskal-Wallis one-way ANOVA on ranks.
resultsSignificantly elevated expression of activated Nrf2 and Ki67 could be detected in PanINs but not in normal pancreatic ductal epithelium. While the effect of Nrf2 on basal cell growth of H6c7-pBp, H6c7-kras and Colo357 cells was minor, it clearly attenuated the growth inhibiting effects of TGF-β1 in all cell lines. This enhanced Nrf2-mediated cell survival was predominantly based on an enhanced proliferative activity. Accordingly, expression of p21 expression along with expression of phospho-p38 and phospho-Smad3 was diminished whereas Erk-phosphorylation was enhanced under these conditions.
conclusionsOverall, our data demonstrate that Nrf2 being elevated in early precursor lesions counteracts the growth inhibiting function of TGF-β1 already in benign and premalignant pancreatic ductal epithelial cells. This could represent one fundamental mechanism underlying the functional switch of both- TGF-β1 and Nrf2 - which may manifest already in early stages of PDAC development.
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