Awano Shuji, Dawson Louise A, Hunter Alison R, Turner Anthony J, Usmani Badar A
Proteolysis Research Group, School of Biochemistry and Microbiology, University of Leeds, Leeds, United Kingdom.
Int J Cancer. 2006 Apr 1;118(7):1645-52. doi: 10.1002/ijc.21525.
The present study focused on the endothelin axis in human oral squamous cell carcinoma (SCC) cells. We investigated the expression and distribution of endothelin-1 (ET-1), its receptors (endothelin-A receptor (ET(A)R) and endothelin-B receptor (ET(B)R)) and isoforms of its specific converting enzyme (ECE-1a, 1b, 1c) and the report on their relative influences on cell proliferation. We also investigated the effect of an ECE-specific inhibitor (ECE-i) and siRNA targeting of the ECE-1 gene on SCC cell proliferation. We observed the expression of ET-1, ET(A)R, ET(B)R and all endothelin-converting enzyme-1 (ECE-1) isoforms in oral SCC cells, but only the expression of ET-1, ET(B)R and ECE-1 was increased when compared to normal human epidermal keratinocytes. ET-1 alone stimulated proliferation of oral SCC cells. Antagonists of either ET(A)R or ET(B)R inhibited ET-1-mediated proliferation. Decreased ECE-1 expression after ECE siRNA treatment reduced SCC cell proliferation. Antiproliferative effects were also observed by inhibiting ECE activity with ECE-i. In conclusion, the present study demonstrates that modulation of the endothelin system in oral SCC cells might provide a novel therapeutic protocol for oral cancer.
本研究聚焦于人类口腔鳞状细胞癌（SCC）细胞中的内皮素轴。我们调查了内皮素-1（ET-1）、其受体（内皮素-A受体（ET(A)R）和内皮素-B受体（ET(B)R））及其特异性转化酶（ECE-1a、1b、1c）同工型的表达和分布，并报告了它们对细胞增殖的相对影响。我们还研究了ECE特异性抑制剂（ECE-i）和靶向ECE-1基因的小干扰RNA（siRNA）对SCC细胞增殖的影响。我们观察到口腔SCC细胞中ET-1、ET(A)R、ET(B)R和所有内皮素转化酶-1（ECE-1）同工型的表达，但与正常人表皮角质形成细胞相比，只有ET-1、ET(B)R和ECE-1的表达增加。单独的ET-1刺激口腔SCC细胞的增殖。ET(A)R或ET(B)R拮抗剂抑制ET-1介导的增殖。ECE siRNA处理后ECE-1表达降低，SCC细胞增殖减少。用ECE-i抑制ECE活性也观察到抗增殖作用。总之，本研究表明，调节口腔SCC细胞中的内皮素系统可能为口腔癌提供一种新的治疗方案。
