Et-1 promotes epithelial–mesenchymal transition in oral squamous cell carcinoma cells via the microrna-489-3p /twist axis

Huey En Tzeng, Chih Hsin Tang, Chun Hao Tsai, Chih Hui Chiu, Min Huan Wu, Yun Yen

Research output: Contribution to journalArticlepeer-review

Abstract

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 vaso-constrictor peptide, is implicated in cancer pathogenesis. Moreover, ET-1 promotes epithe-lial-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.

Original languageEnglish
Pages (from-to)5005-5018
Number of pages14
JournalOncoTargets and Therapy
Volume14
DOIs
Publication statusPublished - 2021

Keywords

  • Endothelin-1
  • Epithelial–mesenchymal transition
  • MicroRNA-489-3p
  • Oral squamous cell carcinoma
  • TWIST

ASJC Scopus subject areas

  • Oncology
  • Pharmacology (medical)

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