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


METHODS
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.
St John
Maie A
MA
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
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
D000818:Animals; D015820:Cadherins / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000494:pharmacology*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects
D015820:Cadherins; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors