Login to Access Video or Poster Abstract: MP98-20
Sources of Funding: none

Introduction

Toll-like receptors (TLRs) play important roles in immune response and have been reported that expression levels of these molecules were related to prognoses of several kinds of cancer. It has been reported that the expression level of TLR4 is reduced in bladder cancer. However, the role of TLR4 in bladder cancer is still unclear. The aim of this study is to clarify the effects of TLR4 expression on prognosis of bladder cancer patients and to elucidate its underlying mechanisms.

Methods

To evaluate the effects of TLR4 expression on prognosis, we analyzed the clinical outcomes of 95 patients with bladder cancer and also conducted immunohistochemistry for TLR4 in bladder cancer specimens. The cancer-specific survival was determined by Kaplan-Meier method and the statistical significance was examined by Log-rank test. We also performed multivariate analysis to evaluate the relationship between TLR4 expression and clinical outcomes. We checked the effects of TLR4 depletion on cell growth and invasive abilities of bladder cancer cells. To clarify the underlying mechanisms, we also analyzed the gene expression profiles in TLR4-depleted cells. These results were validated by quantitative RT-PCR. We also confirmed our finding by using data from public database.

Results

The expression levels of TLR4 were inversely correlated with local invasion and worse prognosis (log-rank test, p=0.007). Although the effect of TLR4 depletion on cell growth was small, it could dramatically enhance invasion ability of cancer cells. We also observed morphologic changes in these cells. Both gene ontology analysis and gene set enrichment analysis of microarray data revealed that most of upregulated genes in TLR4-depleated cells were related to differentiation of epithelium cells. Among these genes, small proline-rich protein (SPRR) family genes which are related to poor prognosis of squamous cell carcinoma were upregulated in TLR4-depleated cells. By analyzing data from public database, we confirmed that expression levels of SPRRs family genes were inversely correlated with TLR4 expression and positively correlated with poor prognosis of bladder cancer patients. Furthermore, we found that expression of TLR4 diminished in the areas with squamous differentiation in bladder cancer.

Conclusions

Our finding suggested that TLR4 is related to bladder cancer aggressiveness through regulation of squamous differentiation.

Funding

none