Abstract
Problem Down regulation of E-cadherin is the hallmark of epithelial mesenchymal transition (EMT). The loss of E-cadherin confers a more invasive phenotype and is one of the steps leading to metastasis. Our recent investigations indicate that inflammatory mediators are potent regulators of EMT in HNSCC. Methods Immunohistochemical analysis of HNSCC tumor tissue specimens, in vitro analysis of E-cadherin regulation in HNSCC cells, and in vivo analysis of tumor growth and metastasis ina murine model. Results An inverse relationship between COX-2 and E-cadherin was demonstrated in situ by double immunohistochemical staining of human HNSCC tissue sections. Treatment of HNSCC cells with exogenous IL-1B, also caused the down regulation of E-cadherin expression and up regulation of Cox-2 expression in HNSCC cell lines in a concentration- and time-dependent manner. IL-1B -treated HNSCC cell lines demonstrated a significant decrease in E-cadherin mRNA and an increase in the mRNA of the transcriptional repressors SNAIL and ZEB1. IL-1B exposure led to enhanced ZEB1 and Snail binding at the chromatin level as determined by chromatin immunoprecipitation assays (ChIP). An inverse relationship between E-cadherin and ZEB1 and a direct relationship between COX-2 and ZEB1 were demonstrated by immunohistochemical staining of human HNSCC tissue sections. When HNSCC cell lines that over express Snail were injected into SCID mice, the primary tumor and metastatic burdens were significantly greater than HNSCC vector controls. Conclusion These findings indicate that 1L-1B modulates transcriptional repressors of E-cadherin and thereby regulates COX-2-dependent E-cadherin expression in HNSCC. This is the first report indicating the role of E-cadherin transcriptional repressors in the inflammation-induced promotion of EMT in HNSCC. Significance This newly defined pathway for transcriptional regulation of E-cadherin in HNSCC has important implications for targeted chemoprevention and therapy. Support AA0–HNS Surgeon Scientist CDA.
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