Abstract
Abstract Objectives: To determine the roles of Snail and p38 in the inflammation-induced promotion of EMT in HNSCC. Study Design: A molecular biology study. Real-time quantitative RT-PCR, Western blot analysis, spheroid modeling, and immunohistochemical staining of human HNSCC tissue sections were used to determine how inflammation affects Snail and p38. Setting: An academic hospital laboratory. Subjects and Methods: Relative RNA levels were determined by RT-PCR, and protein expression was evaluated by immunofluorescence (IF) and in situ by immunohistochemical staining of human HNSCC tissue sections. Results: p38 kinase inhibitor treated, and p38 shRNA HNSCC cell lines demonstrated a significant upregulation in E-cadherin mRNA and a decrease in the mRNA expression of the transcriptional repressor Snail. p38 shRNA HNSCC cell lines show a less invasive phenotype in a spheroid model. An inverse relationship between p38 and E-cadherin was demonstrated in situ by immunohistochemical staining of human HNSCC tissue sections. p38 is required for the robust IL-1β induced E-cadherin downregulation and Snail upregulation. IL-1β increases p-p38 and has a more rapid and robust effect on p38 in Snail overexpressing cell lines. Conclusions: In gastrulation, it is a Snail-independent pathway in which p38 is required in the primitive streak to downregulate E-cadherin expression at the posttranscriptional level. Herein we provide the first report that p38 is required for the Snail-induced E-cadherin down-regulation and cell invasion in HNSCC. A Snail-p38 feedback loop jointly down regulates E-cadherin and drives a potent EMT in HNSCC. This newly defined pathway has important implications for targeted chemoprevention and therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3432. doi:10.1158/1538-7445.AM2011-3432
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