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Activation of STAT3 is a key event in TLR4 signaling-mediated melanoma progression.
- Source :
-
Cell death & disease [Cell Death Dis] 2020 Apr 20; Vol. 11 (4), pp. 246. Date of Electronic Publication: 2020 Apr 20. - Publication Year :
- 2020
-
Abstract
- Malignant melanoma is aggressive and has a high mortality rate. Toll-like receptor 4 (TLR4) has been linked to melanoma growth, angiogenesis and metastasis. However, signal transduction mediated by TLR4 for driving melanoma progression is not fully understood. Signal transducer and activator of transcription 3 (STAT3) has been identified as a major oncogene in melanoma progression. We found: that TLR4 expression positively correlates with activation/phosphorylation of STAT3 in human melanoma samples; that TLR4 ligands activate STAT3 through MYD88 and TRIF in melanoma cells; and that intratumoral activation of TLR4 increases STAT3 activation in the tumor and promotes tumor growth, angiogenesis, epithelial-mesenchymal transition (EMT) and the formation of an immunosuppressive tumor microenvironment in mice. Further, we found that the effects mediated by activating TLR4 are weakened by suppressing STAT3 function with a dominant negative STAT3 variant in melanoma. Collectively, our work identifies STAT3 activation as a key event in TLR4 signaling-mediated melanoma progression, shedding new light on the pathophysiology of melanoma.
- Subjects :
- Cell Line, Tumor
Cell Movement drug effects
Humans
Lipopolysaccharides pharmacology
Melanoma metabolism
Neovascularization, Pathologic drug therapy
Tumor Microenvironment drug effects
Melanoma drug therapy
STAT3 Transcription Factor metabolism
Signal Transduction drug effects
Toll-Like Receptor 4 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 11
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 32312954
- Full Text :
- https://doi.org/10.1038/s41419-020-2440-1