Restoration of E-cadherin expression by selective Cox-2 inhibition and the clinical relevance of the epithelial-to-mesenchymal transition in head and neck squamous cell carcinoma

Journal of Experimental & Clinical Cancer Research

Kaoru Ogawa³  Masato Fujii⁴  Kaori Kameyama⁵  Toshiki Tomita³  Hiroyuki Ozawa⁶  Yoshihiro Watanabe³  Yoichiro Sato³  Kuninori Otsuka³  Noboru Habu³  Seiji Shigetomi²  Koji Sakamoto⁷  Nobuya Sakai¹  Katsushi Shibata¹  Yorihisa Imanishi³  Ryoichi Fujii³ 

[1] Department of Functional Genomics, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Japan;Department of Otorhinolaryngology, Kawasaki Municipal Hospital, Kawasaki, Japan;Department of Otorhinolaryngology-Head and Neck Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan;National Institute of Sensory Organs, National Tokyo Medical Center, Tokyo, Japan;Department of Pathology, Keio University School of Medicine, Tokyo, Japan;Department of Otorhinolaryngology-Head and Neck Surgery, Keiyu Hospital, Yokohama, Japan;Department of Otorhinolaryngology, Saiseikai Utsunomiya Hospital, Utsunomiya, Japan

关键词: Lymph node metastasis;    Epithelial-to-mesenchymal transition (EMT);    Head and neck squamous cell carcinoma (HNSCC);    Cox-2 inhibition;    E-cadherin;   

Others  :  802673
DOI  :  10.1186/1756-9966-33-40

 received in 2014-03-21, accepted in 2014-05-03,  发布年份 2014

【 摘 要 】

Background

The epithelial-to-mesenchymal transition (EMT) accompanied by the downregulation of E-cadherin has been thought to promote metastasis. Cyclooxygenase-2 (Cox-2) is presumed to contribute to cancer progression through its multifaceted function, and recently its inverse relationship with E-cadherin was suggested. The aim of the present study was to investigate whether selective Cox-2 inhibitors restore the expression of E-cadherin in head and neck squamous cell carcinoma (HNSCC) cells, and to examine the possible correlations of the expression levels of EMT-related molecules with clinicopathological factors in HNSCC.

Methods

We used quantitative real-time PCR to examine the effects of three selective Cox-2 inhibitors, i.e., celecoxib, NS-398, and SC-791 on the gene expressions of E-cadherin (CDH-1) and its transcriptional repressors (SIP1, Snail, Twist) in the human HNSCC cell lines HSC-2 and HSC-4. To evaluate the changes in E-cadherin expression on the cell surface, we used a flowcytometer and immunofluorescent staining in addition to Western blotting. We evaluated and statistically analyzed the clinicopathological factors and mRNA expressions of Cox-2, CDH-1 and its repressors in surgical specimens of 40 patients with tongue squamous cell carcinoma (TSCC).

Results

The selective Cox-2 inhibitors upregulated the E-cadherin expression on the cell surface of the HNSCC cells through the downregulation of its transcriptional repressors. The extent of this effect depended on the baseline expression levels of both E-cadherin and Cox-2 in each cell line. A univariate analysis showed that higher Cox-2 mRNA expression (p = 0.037), lower CDH-1 mRNA expression (p = 0.020), and advanced T-classification (p = 0.036) were significantly correlated with lymph node metastasis in TSCC. A multivariate logistic regression revealed that lower CDH-1 mRNA expression was the independent risk factor affecting lymph node metastasis (p = 0.041).

Conclusions

These findings suggest that the appropriately selective administration of certain Cox-2 inhibitors may have an anti-metastatic effect through suppression of the EMT by restoring E-cadherin expression. In addition, the downregulation of CDH-1 resulting from the EMT may be closely involved in lymph node metastasis in TSCC.

【 授权许可】

   
2014 Fujii et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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Figure 3.

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