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01.12.2014 | Research | Ausgabe 1/2014 Open Access

Journal of Experimental & Clinical Cancer Research 1/2014

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 > Ausgabe 1/2014
Ryoichi Fujii, Yorihisa Imanishi, Katsushi Shibata, Nobuya Sakai, Koji Sakamoto, Seiji Shigetomi, Noboru Habu, Kuninori Otsuka, Yoichiro Sato, Yoshihiro Watanabe, Hiroyuki Ozawa, Toshiki Tomita, Kaori Kameyama, Masato Fujii, Kaoru Ogawa
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1756-9966-33-40) contains supplementary material, which is available to authorized users.
Ryoichi Fujii, Yorihisa Imanishi contributed equally to this work.

Competing interests

There are no financial or other relationships that may lead to a conflict of interests.

Authors’ contributions

RF and YI (contributed equally) conceived of and designed the study, conducted the experiments, performed the data analysis, and drafted the manuscript. KS and NS carried out the experiments. KS, SS, NH, and KOt participated in the design of the study and conducted the experiments. YS and YW supported the experiments and the data analysis. KK provided and reviewed the histopathological diagnosis of clinical specimens. HO, TT, and MF participated in the design of the study and the data analysis. KOg provided general support to conception of the study. All authors read and approved the final manuscript.



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.


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).


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).


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.
Authors’ original file for figure 1
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