title: The Crosstalk between Nrf2 and TGF-β1 in the Epithelial-Mesenchymal Transition of Pancreatic Duct Epithelial Cells.
abstract: 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.
authors.affiliation: Laboratory of Molecular Gastroenterology, Dept. of Internal Medicine I, UKSH Campus Kiel, Arnold-Heller-Str. 3, Bldg. 6, 24105, Kiel, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Arfmann-Knübel
authors.affiliation: Laboratory of Molecular Gastroenterology, Dept. of Internal Medicine I, UKSH Campus Kiel, Arnold-Heller-Str. 3, Bldg. 6, 24105, Kiel, Germany.
authors.forename: Birte
authors.initials: B
authors.lastname: Struck
authors.affiliation: Group Inflammatory Carcinogenesis, Institute of Experimental Medicine, CAU Kiel, Arnold-Heller-Str. 3, Bldg. 17, 24105, Kiel, Germany.
authors.forename: Geeske
authors.initials: G
authors.lastname: Genrich
authors.affiliation: Group Inflammatory Carcinogenesis, Institute of Experimental Medicine, CAU Kiel, Arnold-Heller-Str. 3, Bldg. 17, 24105, Kiel, Germany.
authors.forename: Ole
authors.initials: O
authors.lastname: Helm
authors.affiliation: Department of Pathology and Neuropathology, University Hospital Tübingen, Liebermeisterstraße 8, 72076, Tübingen, Germany.
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.affiliation: Group Inflammatory Carcinogenesis, Institute of Experimental Medicine, CAU Kiel, Arnold-Heller-Str. 3, Bldg. 17, 24105, Kiel, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Sebens
authors.affiliation: Laboratory of Molecular Gastroenterology, Dept. of Internal Medicine I, UKSH Campus Kiel, Arnold-Heller-Str. 3, Bldg. 6, 24105, Kiel, Germany.
authors.forename: Heiner
authors.initials: H
authors.lastname: Schäfer
mesh_terms: D001665:Binding Sites / Q000235:genetics; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D020935:MAP Kinase Signaling System; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010183:Pancreatic Ducts / Q000166:cytology / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050500:Pancreatitis, Chronic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D051785:Smad Proteins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D015820:Cadherins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D051785:Smad Proteins; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1