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The Janus kinase 1 is critical for pancreatic cancer initiation and progression. Cell Rep 2024 May 28;43(5):114202

Date

05/11/2024

Pubmed ID

38733583

Pubmed Central ID

PMC11194014

DOI

10.1016/j.celrep.2024.114202

Scopus 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 KU



MESH terms used to index this publication - Major topics in bold

Animals
CCAAT-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