Hyaluronan fragments induce cytokine and metalloprotease upregulation in human melanoma cells in part by signalling via TLR4.
Small fragments of the extracellular matrix component hyaluronic acid (sHA) are typically produced at sites of inflammation and tissue injury and have been shown to be associated with tumor invasiveness and metastasis. Here we report that exposure of human melanoma cells to sHA leads to nuclear factor kB (NFk-B) activation followed by enhanced expression of matrix metalloprotease (MMP) 2 and interleukin (IL)-8, factors that can contribute to melanoma progression. At the receptor level, we found that Toll-like receptor (TLR) 4 is involved in this signalling pathway, similar to the case in dendritic and endothelial cells. Specifically, we found that melanoma cells expressed TLR4 on their surface in vivo and in vitro, and using specific siRNA, we could clearly demonstrate the functional importance of TLR4 in sHA-triggered activation of IL-8 expression in melanoma cells. Furthermore, we also found that sHA treatment enhanced the motility of melanoma cells, an effect that could again be blocked by TLR4-specific siRNA. Together, our results suggest that sHA in melanoma might promote tumor invasiveness by inducing MMP- and cytokine-expression, in part in a TLR4-dependent manner, providing new insights into the relationship between cancer and innate immunity.
Voelcker
Verena
V
Department of Dermatology, Venerology and Allergology, Leipzig University, Leipzig, Germany. verena_voelcker@hotmail.com
Gebhardt
Carl
C
Averbeck
Marco
M
Saalbach
Anja
A
Wolf
Verena
V
Weih
Falk
F
Sleeman
Jonathan
J
Anderegg
Ulf
U
Simon
Jan
J
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D018450:Disease Progression; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology*; D007113:Immunity, Innate / Q000502:physiology; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D000276:Adjuvants, Immunologic; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D006820:Hyaluronic Acid; D020778:Matrix Metalloproteinase 2