title: Paracrine IL-6 signaling mediates the effects of pancreatic stellate cells on epithelial-mesenchymal transition via Stat3/Nrf2 pathway in pancreatic cancer cells.
abstract: We previously showed that pancreatic stellate cells (PSC) secreted interleukin (IL)-6 and promoted pancreatic ductal adenocarcinoma (PDAC) cell proliferation via nuclear factor erythroid 2 (Nrf2)-mediated metabolic reprogramming. Epithelial-mesenchymal transition (EMT) is a key process for the metastatic cascade. To study the mechanism of PDAC progression to metastasis, we investigated the role of PSC-secreted IL-6 in activating EMT and the involvement of Nrf2 in this process.
  
  
  
  Gene expression of IL-6 and IL-6Rα in PSC and PDAC cells was measured with qRT-PCR. The role of PSC-secreted IL-6, JAK/Stat3 signaling, and Nrf2 mediation on EMT-related genes expression was also examined with qRT-PCR. EMT phenotypes were assessed with morphological change, wound healing, migration, and invasion.
  
  
  
  PSC expressed higher mRNA levels of IL-6 but lower IL-6Rα compared to PDAC cells. Neutralizing IL-6 in PSC secretion reduced mesenchymal-like morphology, migration and invasion capacity, and mesenchymal-like gene expression of N-cadherin, vimentin, fibronectin, collagen I, Sip1, Snail, Slug, and Twist2. Inhibition of JAK/Stat3 signaling induced by IL-6 repressed EMT and Nrf2 gene expression. Induction of Nrf2 activity by tert-butylhydroquinone (tBHQ) increased both EMT phenotypes and gene expression (N-cadherin, fibronectin, Twist2, Snail, and Slug) repressed by IL-6 neutralizing antibody. Simultaneous inhibition of Nrf2 expression with siRNA and Stat3 signaling further repressed EMT gene expression, indicating that Stat3/Nrf2 pathway mediates EMT induced by IL-6.
  
  
  
  IL-6 from PSC promotes EMT in PDAC cells via Stat3/Nrf2 pathway.
  
  
  
  Targeting Stat3/Nrf2 pathway activated by PSC-secreted IL-6 may provide a novel therapeutic option to improve the prognosis of PDAC.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia; University of Malaya Cancer Research Institute, University of Malaya, Kuala Lumpur 50603, Malaysia.
authors.forename: Yuan Seng
authors.initials: YS
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia; University of Malaya Cancer Research Institute, University of Malaya, Kuala Lumpur 50603, Malaysia.
authors.forename: Ivy
authors.initials: I
authors.lastname: Chung
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia.
authors.forename: Won Fen
authors.initials: WF
authors.lastname: Wong
authors.affiliation: Division of Gastroenterology, Tohoku University of Graduate School of Medicine, Sendai, Miyagi Prefecture 980-8574, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Masamune
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia.
authors.forename: Maw Shin
authors.initials: MS
authors.lastname: Sim
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia. Electronic address: chungyeng@gmail.com.
authors.forename: Chung Yeng
authors.initials: CY
authors.lastname: Looi
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000378:metabolism / Q000473:pathology*; D019899:Paracrine Communication / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: Cancer-associated fibroblasts; Cytokines; Mechanism; Metastasis; Pancreatic ductal adenocarcinoma; Tumor microenvironment