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

Abstract

BackgroundThe 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.MethodsWe 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).ResultsThe 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).ConclusionsThese 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.

Expression profiles of selected genes in tumors and matched surgical margins in oral cavity cancer: Do we have to pay attention to the molecular analysis of the surgical margins?

“…42 In a study conducted on clinical samples collected from patients with tongue squamous cell carcinoma, a significantly lower CDH1 mRNA expression level than in the corresponding noncancerous tissues was shown. 31 In our study, no significant differences were found between the CDH1 gene expression levels of the tumors and the surgical margin samples. Similar results were obtained by Kordi-Tamandani et al, who found no significant differences between the mRNA expression of the CDH1 gene of patients with oral cavity cancer and that of a healthy control group.…”

The selective cyclooxygenase‐2 inhibitor mavacoxib (Trocoxil) exerts anti‐tumour effects in vitro independent of cyclooxygenase‐2 expression levels

“…In human bladder cancer, the T24 cell line exhibits a strong EMT phenotype which can be reversed by the COX‐2 inhibitor etodolac . Che et al (2017) have demonstrated in lung cancer cells that migration and invasion are stimulated via interleukin‐6 (IL‐6) upregulation of COX‐2/PGE 2 , with a similar finding in head and neck squamous cell carcinoma . In this study, we report that mavacoxib can inhibit migration of a panel of canine and human cancer cell lines and that this action is cell line dependent.…”

New Insights on COX-2 in Chronic Inflammation Driving Breast Cancer Growth and Metastasis

“…Thus, Celecoxib was found to be effective in upregulating E-cadherin thus reversing the EMT in cell lines derived from head and neck squamous cancer, colon cancer, gastric cancer and breast cancer [101][102][103][104]. Another COX-2 inhibitor, Etodolac, had a similar effect in bladder cancer cell lines, where EMT reversal was also seen in vivo in xenografts of the human bladder cancer cell line T24 [105].…”

“…In bladder and breast cancer the E-cadherin gene is induced by COX-2 appears to be Snail1 [96,105], in non-small cell lung cancer COX-2 induced Snail1 and Zeb1 [108], whereas in head and neck squamous cancer COX-2 induced Snail1, SIP1/Zeb2 as well as Twist1 [101].…”