Tzeng Huey-En, Tang Chih-Hsin, Tsai Chun-Hao, Chiu Chih-Hui, Wu Min-Huan, Yen Yun
Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan.
PhD Program & Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Onco Targets Ther. 2021 Oct 6;14:5005-5018. doi: 10.2147/OTT.S294312. eCollection 2021.
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.
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.
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.
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.
口腔鳞状细胞癌（OSCC）几乎占头颈部恶性肿瘤的90%，预后较差。为提高OSCC的治疗效果，探索OSCC的其他治疗方法具有重要意义。内皮素-1（ET-1）是一种有效的血管收缩肽，与癌症发病机制有关。此外，ET-1在人类癌症发展过程中促进上皮-间质转化（EMT）。我们进一步发现，ET-1处理通过上调转录因子TWIST增强EMT生物标志物N-钙黏蛋白和波形蛋白的表达并降低E-钙黏蛋白的表达，从而诱导人鳞状细胞癌细胞系SCC4和SAS发生EMT。
通过迁移、侵袭和伤口愈合试验检测细胞运动能力。定量实时聚合酶链反应（q-PCR）和启动子分析证实了ET-1对口腔癌细胞中微小RNA（miRNA）表达的抑制作用。我们展示了一种肺转移的静脉注射模型，随后是一种使用图像分析软件定量转移性肿瘤的先进方法。
此外，ET-1/ETAR降低了TWIST的转录抑制因子微小RNA-489-3p（miR-489-3p）的水平。我们确定了一种新的旁路机制，通过该机制ET-1/ETAR参与TWIST信号传导并下调miR-489-3p表达，使OSCC细胞获得EMT表型。值得注意的是，ET-1基因敲低显著降低了EMT标志物的水平和细胞迁移潜力。
我们在OSCC小鼠体内模型中的研究结果支持了ET-1在OSCC进展中的作用。因此，ET-1可能是OSCC转移的一个新的分子治疗靶点。
