OncoTargets and Therapy (Oct 2021)
ET-1 Promotes Epithelial–Mesenchymal Transition in Oral Squamous Cell Carcinoma Cells via the microRNA-489-3p /TWIST Axis
Abstract
Huey-En Tzeng,1– 3 Chih-Hsin Tang,4– 7 Chun-Hao Tsai,8 Chih-Hui Chiu,9 Min-Huan Wu,10,11 Yun Yen12,13 1Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan; 2PhD Program & Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; 3Division of Hematology/Oncology, Department of Medicine, Taipei Medical University Hospital, Taipei, Taiwan; 4Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; 5School of Medicine, China Medical University, Taichung, Taiwan; 6Chinese Medicine Research Center, China Medical University, Taichung, Taiwan; 7Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan; 8Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan; 9Graduate Program in Department of Exercise Health Science, National Taiwan University of Sport, Taichung, Taiwan; 10Sports Recreation and Health Management Continuing Studies, Tunghai University, Taichung, Taiwan; 11Bachelor of Science in Senior Wellness and Sport Science, Tunghai University, Taichung, Taiwan; 12TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; 13Graduate Institute of Medical Informatics, Taipei Medical University, Taipei, TaiwanCorrespondence: Min-Huan Wu Tel +886 4-23590121 Ext. 30703Email [email protected] Yen Email [email protected]: 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.Keywords: oral squamous cell carcinoma, endothelin-1, TWIST, microRNA-489-3p, epithelial–mesenchymal transition
