Abstract
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 cells 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 play a role in decorin silencing mediated reduction in IL-8 levels. We have used immunological and molecular techniques to study toll-like receptors involvement in attenuated IL-8 production in nuclear decorin silenced (stable knockdown) oral mucosal dysplastic keratinocytes and squamous carcinoma cells. We show that nuclear decorin silenced DOK and SCC-25 cells show marked diminution of TLR5 mRNA and protein expression compared with respective controls that translated into 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 in mucosal cancers.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is a devastating disease that accounts for roughly 1.6 million newly diagnosed cases and 330,000 deaths each year worldwide [1,2]; half of these cancers are localized in the oral cavity and are termed oral squamous cell carcinoma
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
Consistent with down regulation of TLR5 expression levels, we found a significant reduction in flagellin stimulated IL-8 production in decorin silenced cells compared to wild type (WT) or ctrl-short hairpin RNA (shRNA) treated dysplastic oral keratinocytes (DOK) or SCC-25 cells (Figure 3)
Summary
Head and neck squamous cell carcinoma (HNSCC) is a devastating disease that accounts for roughly 1.6 million newly diagnosed cases and 330,000 deaths each year worldwide [1,2]; half of these cancers are localized in the oral cavity and are termed oral squamous cell carcinoma. TLRs are predominantly expressed on various immune and structural cells where they serve as innate cell surface pathogen sensors and promote local inflammation by triggering the induction of various proinflammatory mediators, including IL-8. TLR expression or up-regulation has been detected in various tumour types, especially in epithelium derived cancers [9,10,11]. Expression of TLRs varies in different cancerous cell types; evidence indi-
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