Proinflammatory mediators upregulate snail in head and neck squamous cell carcinoma.
Proinflammatory mediators upregulate snail in head and neck squamous cell carcinoma.
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促炎性介质在头部和颈部鳞状细胞癌中上调蜗牛。
DOI：
10.1158/1078-0432.ccr-09-0011
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发表时间：
2009-10-01
期刊：
影响因子：
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通讯作者：
Dubinett SM
中科院分区：
文献类型：
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作者：
St John MA;Dohadwala M;Luo J;Wang G;Lee G;Shih H;Heinrich E;Krysan K;Walser T;Hazra S;Zhu L;Lai C;Abemayor E;Fishbein M;Elashoff DA;Sharma S;Dubinett SM
炎症细胞因子参与了HNSCC的进展。在本研究中，我们探讨了IL-1β在鼻咽癌上皮细胞转化中的作用机制。我们评价了IL-1β对手术标本和人喉鳞状细胞癌细胞系上皮细胞转化分子事件的影响。我们研究了与肿瘤组织学特征的相关性，并使用SCID异种移植模型来评估Snail过表达的影响。COX-2依赖的信号通路参与调控HNSCC中E-钙粘蛋白的表达。HNSCC组织切片双重免疫组织化学染色显示COX-2和E-钙粘蛋白的表达呈负相关。IL-1β作用于HNSCC细胞后，E-钙粘附素表达下调，COX-2表达上调。这种作用在COX-2 shRNA存在的情况下被阻断。经IL-1β处理的人喉鳞状细胞癌细胞株E-钙粘蛋白基因表达显著降低，转录抑制因子Snail的基因表达增强。IL-1β暴露导致染色质水平上的蜗牛结合增强。ShRNA介导的Snail基因敲除阻断了IL-1β下调E-钙粘附素的能力。在SCID异种移植模型中，HNSCC Snail过表达细胞显著增加了原发和转移的肿瘤负担。IL-1β调节Snail，从而调节HNSCC中COX-2依赖的E-钙粘素的表达。这是第一个表明Snail在炎症诱导的HNSCC中促进EMT的作用的报告。这一新定义的E-钙粘蛋白转录调控途径对HNSCC的靶向化学预防和治疗具有重要意义。
Inflammatory cytokines have been implicated in the progression of HNSCC. Herein we investigate the mechanisms by which IL-1β might contribute to EMT in HNSCC. We evaluated the effect of IL-1β 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. COX-2-dependent pathways contribute to the modulation of E-cadherin expression in HNSCC. 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 IL-1β, caused the downregulation of E-cadherin expression and upregulation of COX-2 expression. This effect was blocked in the presence of COX-2 shRNA. IL-1β -treated HNSCC cell lines demonstrated a significant decrease in E-cadherin mRNA and an increase in the mRNA expression of the transcriptional repressor Snail. IL-1β exposure led to enhanced Snail binding at the chromatin level. ShRNA-mediated knockdown of Snail interrupted the capacity of IL-1β to downregulate E-cadherin. In a SCID xenograft model, HNSCC Snail overexpressing cells demonstrated significantly increased primary and metastatic tumor burdens. IL-1β 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.