Role of toll-like receptor 4 on the immune escape of human oral squamous cell carcinoma and resistance of cisplatin-induced apoptosis

Zujun Sun,Fuxiang Chen,Wantao Chen,Dongxia Ye,Qingqiong Luo

doi:10.1186/1476-4598-11-33

Abstract

BackgroundToll-like receptor 4 (TLR4) is expressed on immune cells as a sensor that recognizes lipopolysaccharide (LPS), a microbial conserved component. It has recently been determined that the expression of TLR4 is also found in various types of tumor cells. Cisplatin is a widely used chemotherapeutic agent for oral squamous cell carcinoma (OSCC) treatment. However, the mechanisms responsible for cisplatin resistance are not well understood.ResultsThe present study was designed to elucidate the role of TLR4 expression in human OSCC regarding immune escape and apoptotic resistance to cisplatin. TLR4 and the myeloid differentiation primary response gene 88 (MyD88) were highly expressed in OSCC cell lines. Upon LPS stimulation both NF-κB and p38 MAPK pathways were activated in OSCC cell lines, followed by the production of large quantities of IL-6, IL-8 and VEGF compared with human immortalized oral epithelia cells (HIOECs). OSCC cell lines were found to be resistant to cisplatin-mediated apoptosis after pretreatment with LPS.ConclusionsOur results suggested that TLR4 was functionally expressed in human OSCC cells and development of resistance to cisplatin in human OSCC might occur through the mechanism involving TLR4 and its signaling pathway. Suppression of TLR4 and its signaling pathway might thus elevate sensitivity to cisplatin and potentially help improve the prognosis of patients with OSCC.

Highlights

Toll-like receptor 4 (TLR4) is expressed on immune cells as a sensor that recognizes lipopolysaccharide (LPS), a microbial conserved component
Expression of TLR4 and myeloid differentiation primary response gene 88 (MyD88) in human oral squamous cell carcinoma (OSCC) tissues and cells To investigate whether TLR4 and its adaptor molecule MyD88 were expressed in human OSCC tissues, 30 human OSCC specimens and 10 normal oral tissue samples adjacent to the tumor were assessed in situ in paraffin sections
TLR4 was found to localize to the cell membrane and cell cytoplasm and MyD88 localized to the cell cytoplasm only

Summary

Introduction

Toll-like receptor 4 (TLR4) is expressed on immune cells as a sensor that recognizes lipopolysaccharide (LPS), a microbial conserved component. It has recently been determined that the expression of TLR4 is found in various types of tumor cells. The role of toll-like receptors (TLRs) and their signaling in tumor immune escape and resistance to apoptosis, for example, is among the frontiers of exploration [3,4]. There have been reports of TLRs in various tumor types, the function of these receptors in OSCC prognosis and resistance to chemotherapy remains unknown [13]. OSCC is sensitive to cisplatin-based chemotherapy in patients with an initial response to treatment. It is important to address the pattern of TLR4 expression on OSCC cell lines and to determine the pathophysiological significance of TLR4 signaling in the immune escape and chemoresistance of OSCC. The purpose of this study was to explore the expression and role of TLR4 in OSCC and how TLR4 signaling correlated with cisplatin resistance in OSCC

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