TLR5 involvement in attenuated IL-8 production in nuclear decorin silenced oral mucosal dysplastic keratinocytes and squamous cell carcinoma

Head and neck cancer is one of the most prevalent cancers in the world. Roughly half of these malignancies originate from oral mucosa and constitute oral squamous cell carcinomas. Despite many advances in diagnostic and therapeutic regimens, five-year survival rate remains at roughly 50%, indicating the need for in depth understanding of the oral squamous cell carcinoma immunobiology. We have previously shown that in human dysplastic oral keratinocytes (DOK) and malignant squamous cell carcinoma (SCC-25), multifunctional proteoglycan decorin is aberrantly expressed and localized in the nucleus bound to nuclear EGFR. In vitro nuclear decorin knockdown significantly reduced IL-8 and IL8-dependent migration, invasion and angiogenesis in these cells. Since toll-like receptor (TLR) signalling leads to IL-8 production, we examined here if these receptors played a role in decorin silencing mediated reduction in IL-8 levels in oral mucosal dysplastic keratinocytes and squamous carcinoma cells. Decorin silenced DOK and SCC-25 cells showed a marked diminution of TLR5 mRNA and protein expression compared with respective controls that translated into the loss of function in response to appropriate TLR ligand. In these mucosal oral epithelia, decorin stable knockdown significantly down-regulated IL-8 production following activation with TLR5 ligand flagellin. These data suggest that decorin silencing interferes with IL-8 production, in part, by altering TLR5 expression and signaling in dysplastic and malignant oral epithelia. This study highlights the significance of TLR5 expression and signaling and its plausible interactions with proteoglycans in mucosal cancers.