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.
Original language | English |
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Article number | 114202 |
Journal | Cell Reports |
Volume | 43 |
Issue number | 5 |
DOIs | |
State | Published - 28 May 2024 |
Externally published | Yes |
Keywords
- CEBPD
- CP: Cancer
- Janus kinase 1
- PDAC
- RNA sequencing
- STAT proteins
- gene targeting
- humans
- mice
- pancreatic cancer
- pancreatic neoplasms
- phosphorylation
- signal transduction
- transcription factor
- transgenic
- tyrosine kinase