Janus Kinase 1 Plays a Critical Role in Mammary Cancer Progression
| Autor: | Patrick D. Rädler, Barbara L. Wehde, Kay Uwe Wagner, Hridaya Shrestha, Aleata A. Triplett, Stevi J. Johnson |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Carcinogenesis Receptor ErbB-2 Breast Neoplasms Biology Ligands MAP3K8 Epithelium Article General Biochemistry Genetics and Molecular Biology Receptor tyrosine kinase 03 medical and health sciences Cell Movement Cell Line Tumor Spheroids Cellular medicine Animals Humans Neoplasm Metastasis Phosphorylation STAT3 lcsh:QH301-705.5 Mice Knockout Janus kinase 1 Cancer Janus Kinase 1 medicine.disease Neoplasm Proteins STAT Transcription Factors 030104 developmental biology lcsh:Biology (General) Disease Progression Cancer research biology.protein STAT protein Female Signal transduction Janus kinase |
| Zdroj: | Cell Reports, Vol 25, Iss 8, Pp 2192-2207.e5 (2018) |
| ISSN: | 2211-1247 |
| Popis: | Summary: Janus kinases (JAKs) and their downstream STAT proteins play key roles in cytokine signaling, tissue homeostasis, and cancer development. Using a breast cancer model that conditionally lacks Janus kinase 1, we show here that JAK1 is essential for IL-6-class inflammatory cytokine signaling and plays a critical role in metastatic cancer progression. JAK1 is indispensable for the oncogenic activation of STAT1, STAT3, and STAT6 in ERBB2-expressing cancer cells, suggesting that ERBB2 receptor tyrosine kinase complexes do not directly activate these STAT proteins in vivo. A genome-wide gene expression analysis revealed that JAK1 signaling has pleiotropic effects on several pathways associated with cancer progression. We established that FOS and MAP3K8 are targets of JAK1/STAT3 signaling, which promotes tumorsphere formation and cell migration. The results highlight the significance of JAK1 as a rational therapeutic target to block IL-6-class cytokines, which are master regulators of cancer-associated inflammation. : Wehde et al. demonstrate that JAK1 is the pivotal kinase that controls cytokine-mediated activation of three STAT proteins in ERBB2-driven mammary cancer cells. They provide experimental evidence that deficiency in JAK1/STAT3 signaling and consequential downregulation of oncogenic targets inhibit migration, tumorsphere formation, and metastatic dissemination of mammary cancer cells. Keywords: breast cancer, mammary neoplasms, Janus kinase 1, Stat transcription factor, gene targeting, signal transduction, Cre recombinase, RNA sequencing, c-Fos, MAP3K8 |
| Databáze: | OpenAIRE |
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