ET-1 Promotes Epithelial-Mesenchymal Transition in Oral Squamous Cell Carcinoma Cells via the microRNA-489-3p /TWIST Axis.

OBJECTIVE

Oral squamous cell carcinoma (OSCC) constitutes almost 90% of head and neck malignancies and has a poor prognosis. To improve the efficacy of OSCC therapy, it is of great significance to explore other therapy for OSCC. Endothelin-1 (ET-1), a potent vasoconstrictor peptide, is implicated in cancer pathogenesis. Moreover, ET-1 promotes epithelial-mesenchymal transition (EMT) during the development of human cancers. We further to found that ET-1 exposure induced EMT in human squamous cell carcinoma cell lines SCC4 and SAS, by enhancing the expression of EMT biomarkers N-cadherin and vimentin and reducing E-cadherin expression via upregulation of the transcription factor TWIST.

MATERIALS AND METHODS

Cell motility was examined by migration, invasion and wound-healing assays. Quantitative real time polymerase chain reaction (q-PCR), and promoter assays confirmed the inhibitory effects of ET-1 on miRNAs expression in oral cancer cells. We demonstrate an intravenous injection model of lung metastasis followed by an advanced method for quantifying metastatic tumor using image analysis software.

RESULTS

In addition, ET-1/ETAR reduced levels of microRNA-489-3p (miR-489-3p), a transcriptional repressor of TWIST. We have identified a novel bypass mechanism through which ET-1/ETAR are involved in TWIST signaling and downregulate miR-489-3p expression, enabling OSCC cells to acquire the EMT phenotype. Notably, ET-1 knockdown dramatically decreased levels of EMT markers and cell migration potential.

CONCLUSION

The role of ET-1 in OSCC progression is supported by our findings from an in vivo murine model of OSCC. ET-1 may therefore represent a novel molecular therapeutic target in OSCC metastasis.