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.
Highlights
Melanoma originated from neural crest-derived melanocytes is an aggressive cancer, with rapid deterioration and high fatality[1]
In this study, our findings provide evidence that Signal transducer and activator of transcription 3 (STAT3) is a key player in Toll-like receptor 4 (TLR4) signaling-mediated melanoma progression
Bald et al demonstrated that ultraviolet (UV)-radiation induces TLR4/MYD88 axis-driven neutrophilic inflammation to promote melanoma angiogenesis and metastasis[5]
Summary
Melanoma originated from neural crest-derived melanocytes is an aggressive cancer, with rapid deterioration and high fatality[1]. The pathogenesis of melanoma is complex and is not fully elucidated to date. Current targeted therapies and immunotherapies for unresectable melanoma are showing exciting clinical results, this disease is still incurable. Understanding the mechanisms of melanoma progression should significantly advance the development of novel therapies for combatting it. Toll-like receptor 4 (TLR4) is a signaling molecule responsible for clearing pathogens[2]. It is linked to the development of multiple cancers including melanoma[3]
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