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Proinflammatory mediators upregulate snail in head and neck squamous cell carcinoma.


ABSTRACT: Inflammatory cytokines have been implicated in the progression of head and neck squamous cell carcinoma (HNSCC). Herein we investigate the mechanisms by which interleukin-1beta (IL-1beta) might contribute to Epithelial-Mesenchymal Transition (EMT) in HNSCC.We evaluated the effect of IL-1beta on the molecular events of EMT in surgical specimens and HNSCC cell lines. We examined the correlation with tumor histologic features, and a SCID xenograft model was used to assess the effects of Snail overexpression.Cyclooxygenase-2 (COX-2)-dependent pathways contribute to the modulation of E-cadherin expression in HNSCC. An inverse relationship between COX-2 and E-cadherin was shown in situ by double immunohistochemical staining of human HNSCC tissue sections. Treatment of HNSCC cells with IL-1beta caused the downregulation of E-cadherin expression and upregulation of COX-2 expression. This effect was blocked in the presence of COX-2 small hairpin RNA. IL-1beta-treated HNSCC cell lines showed a significant decrease in E-cadherin mRNA and an increase in the mRNA expression of the transcriptional repressor Snail. IL-1beta exposure led to enhanced Snail binding at the chromatin level. Small hairpin RNA-mediated knockdown of Snail interrupted the capacity of IL-1beta to downregulate E-cadherin. In a SCID xenograft model, HNSCC Snail-overexpressing cells showed significantly increased primary and metastatic tumor burdens.IL-1beta modulates Snail and thereby regulates COX-2-dependent E-cadherin expression in HNSCC. This is the first report indicating the role of Snail in the inflammation-induced promotion of EMT in HNSCC. This newly defined pathway for transcriptional regulation of E-cadherin in HNSCC has important implications for targeted chemoprevention and therapy.

SUBMITTER: St John MA 

PROVIDER: S-EPMC2782528 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Proinflammatory mediators upregulate snail in head and neck squamous cell carcinoma.

St John Maie A MA   Dohadwala Mariam M   Luo Jie J   Wang Guanyu G   Lee Gina G   Shih Hubert H   Heinrich Eileen E   Krysan Kostantyn K   Walser Tonya T   Hazra Saswati S   Zhu Li L   Lai Chi C   Abemayor Elliot E   Fishbein Michael M   Elashoff David A DA   Sharma Sherven S   Dubinett Steven M SM  

Clinical cancer research : an official journal of the American Association for Cancer Research 20090929 19


<h4>Purpose</h4>Inflammatory cytokines have been implicated in the progression of head and neck squamous cell carcinoma (HNSCC). Herein we investigate the mechanisms by which interleukin-1beta (IL-1beta) might contribute to Epithelial-Mesenchymal Transition (EMT) in HNSCC.<h4>Experimental design</h4>We evaluated the effect of IL-1beta on the molecular events of EMT in surgical specimens and HNSCC cell lines. We examined the correlation with tumor histologic features, and a SCID xenograft model w  ...[more]

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