The Janus kinase 1 is critical for pancreatic cancer initiation and progression. Cell Rep 2024 May 28;43(5):114202
Date
05/11/2024Pubmed ID
38733583Pubmed Central ID
PMC11194014DOI
10.1016/j.celrep.2024.114202Scopus ID
2-s2.0-85192447874 (requires institutional sign-in at Scopus site)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 KRASG12D-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.
Author List
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, Wagner KUMESH terms used to index this publication - Major topics in bold
AnimalsCCAAT-Enhancer-Binding Protein-delta
Carcinoma, Pancreatic Ductal
Cell Line, Tumor
Disease Progression
Humans
Janus Kinase 1
Mice
Mice, Knockout
Pancreatic Neoplasms
STAT3 Transcription Factor
Signal Transduction