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

Autor: Anna Broich, Ole Helm, Sandra Freitag-Wolf, Bence Sipos, Heiner Schäfer, Christoph Röcken, Lennart Lenk, Geeske Genrich, Susanne Sebens, Marcus Kruppa
Rok vydání: 2015
Předmět:
0301 basic medicine
Pathology
Cancer Research
Cell
Proliferation
Pancreatic Intraepithelial Neoplasia
Gene Expression
Apoptosis
Smad Proteins
medicine.disease_cause
environment and public health
0302 clinical medicine
TGF-β1
respiratory system
medicine.anatomical_structure
Cell Transformation
Neoplastic
Oncology
030220 oncology & carcinogenesis
Gene Knockdown Techniques
Mitogen-Activated Protein Kinases
Chronic pancreatitis
Carcinoma
Pancreatic Ductal
Protein Binding
Signal Transduction
Research Article
medicine.medical_specialty
Cell signaling
NF-E2-Related Factor 2
digestive system
Transforming Growth Factor beta1
03 medical and health sciences
Pancreatic cancer
Cell Line
Tumor
medicine
Genetics
Humans
Cell damage
Cell Proliferation
Cell growth
business.industry
Pancreatic Ducts
Epithelial Cells
medicine.disease
Pancreatic Neoplasms
Oxidative Stress
030104 developmental biology
Ki-67 Antigen
Cancer research
Pancreatic cancer precursor lesion
business
Carcinogenesis
Precancerous Conditions
Transforming growth factor
Zdroj: BMC Cancer
ISSN: 1471-2407
Popis: Background Nuclear 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. Methods In 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. Results Significantly 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. Conclusions Overall, 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. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2191-7) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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