The Crosstalk between Nrf2 and TGF-β1 in the Epithelial-Mesenchymal Transition of Pancreatic Duct Epithelial Cells

Autor: Ole Helm, Susanne Sebens, Geeske Genrich, Bence Sipos, Sarah Arfmann-Knübel, Heiner Schäfer, Birte Struck
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Pathology
medicine.medical_specialty
Epithelial-Mesenchymal Transition
MAP Kinase Signaling System
NF-E2-Related Factor 2
lcsh:Medicine
Vimentin
Smad Proteins
Biology
medicine.disease_cause
digestive system
environment and public health
Malignant transformation
Cell Line
Transforming Growth Factor beta1
Cell Line
Tumor
Pancreatitis
Chronic
medicine
Humans
Neoplasm Invasiveness
Epithelial–mesenchymal transition
lcsh:Science
Promoter Regions
Genetic
Pancreatic duct
Multidisciplinary
Binding Sites
lcsh:R
Pancreatic Ducts
Epithelial Cells
respiratory system
Cadherins
Cytoprotection
Pancreatic Neoplasms
medicine.anatomical_structure
Cell culture
Gene Knockdown Techniques
Cancer research
biology.protein
lcsh:Q
Pancreas
Carcinogenesis
Precancerous Conditions
Research Article
Carcinoma
Pancreatic Ductal
Zdroj: PLoS ONE
PLoS ONE, Vol 10, Iss 7, p e0132978 (2015)
ISSN: 1932-6203
Popis: Nrf2 and TGF-β1 both affect tumorigenesis in a dual fashion, either by preventing carcinogen induced carcinogenesis and suppressing tumor growth, respectively, or by conferring cytoprotection and invasiveness to tumor cells during malignant transformation. Given the involvement of Nrf2 and TGF-β1 in the adaptation of epithelial cells to persistent inflammatory stress, e.g. of the pancreatic duct epithelium during chronic pancreatitis, a crosstalk between Nrf2 and TGF-β1 can be envisaged. By using premalignant human pancreatic duct cells (HPDE) and the pancreatic ductal adenocarcinoma cell line Colo357, we could show that Nrf2 and TGF-β1 independently but additively conferred an invasive phenotype to HPDE cells, whereas acting synergistically in Colo357 cells. This was accompanied by differential regulation of EMT markers like vimentin, Slug, L1CAM and E-cadherin. Nrf2 activation suppressed E-cadherin expression through an as yet unidentified ARE related site in the E-cadherin promoter, attenuated TGF-β1 induced Smad2/3-activity and enhanced JNK-signaling. In Colo357 cells, TGF-β1 itself was capable of inducing Nrf2 whereas in HPDE cells TGF-β1 per-se did not affect Nrf2 activity, but enhanced Nrf2 induction by tBHQ. In Colo357, but not in HPDE cells, the effects of TGF-β1 on invasion were sensitive to Nrf2 knock-down. In both cell lines, E-cadherin re-expression inhibited the proinvasive effect of Nrf2. Thus, the increased invasion of both cell lines relates to the Nrf2-dependent downregulation of E-cadherin expression. In line, immunohistochemistry analysis of human pancreatic intraepithelial neoplasias in pancreatic tissues from chronic pancreatitis patients revealed strong Nrf2 activity already in premalignant epithelial duct cells, accompanied by partial loss of E-cadherin expression. Our findings indicate that Nrf2 and TGF-β1 both contribute to malignant transformation through distinct EMT related mechanisms accounting for an invasive phenotype. Provided a crosstalk between both pathways, Nrf2 and TGF-β1 mutually promote their tumorigenic potential, a condition manifesting already at an early stage during inflammation induced carcinogenesis of the pancreas.
Databáze: OpenAIRE
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