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Clin Cancer Res. 2009 Oct 1;15(19):6018-27. doi: 10.1158/1078-0432.CCR-09-0011. Epub 2009 Sep 29.

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

Author information

1
Division of Head and Neck Surgery, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA. mstjohn@mednet.ucla.edu

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

RESULTS:

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.

CONCLUSIONS:

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.

PMID:
19789323
PMCID:
PMC2782528
DOI:
10.1158/1078-0432.CCR-09-0011
[Indexed for MEDLINE]
Free PMC Article

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