1. The Janus kinase 1 is critical for pancreatic cancer initiation and progression.
- Author
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Shrestha H, Rädler PD, Dennaoui R, Wicker MN, Rajbhandari N, Sun Y, Peck AR, Vistisen K, Triplett AA, Beydoun R, Sterneck E, Saur D, Rui H, and Wagner KU
- Subjects
- Animals, Humans, Mice, CCAAT-Enhancer-Binding Protein-delta metabolism, CCAAT-Enhancer-Binding Protein-delta genetics, Cell Line, Tumor, Disease Progression, Mice, Knockout, Signal Transduction, STAT3 Transcription Factor metabolism, Carcinoma, Pancreatic Ductal pathology, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal metabolism, Janus Kinase 1 metabolism, Janus Kinase 1 genetics, Pancreatic Neoplasms pathology, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism
- Abstract
Interleukin-6 (IL-6)-class inflammatory cytokines signal through the Janus tyrosine kinase (JAK)/signal transducer and activator of transcription (STAT) pathway and promote the development of pancreatic ductal adenocarcinoma (PDAC); however, the functions of specific intracellular signaling mediators in this process are less well defined. Using a ligand-controlled and pancreas-specific knockout in adult mice, we demonstrate in this study that JAK1 deficiency prevents the formation of KRAS
G12D -induced pancreatic tumors, and we establish that JAK1 is essential for the constitutive activation of STAT3, whose activation is a prominent characteristic of PDAC. We identify CCAAT/enhancer binding protein δ (C/EBPδ) as a biologically relevant downstream target of JAK1 signaling, which is upregulated in human PDAC. Reinstating the expression of C/EBPδ was sufficient to restore the growth of JAK1-deficient cancer cells as tumorspheres and in xenografted mice. Collectively, the findings of this study suggest that JAK1 executes important functions of inflammatory cytokines through C/EBPδ and may serve as a molecular target for PDAC prevention and treatment., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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