Bioactive Lipid Research Program, Department of Pathology, Wayne State University School of Medicine, 423 Chemistry Building, Detroit, MI 48202, USA.
Int J Oncol. 2012 May;40(5):1619-26. doi: 10.3892/ijo.2012.1379. Epub 2012 Feb 16.
Sphingosine-1-phosphate (S1P) regulates a wide array of biological functions. However, the role of S1P signaling in tumorigenesis remains to be elucidated. In this study, we show that S1P receptor subtype 3 (S1P₃) is markedly up-regulated in a subset of lung adenocarcinoma cells compared to normal lung epithelial cells. Specific knockdown of S1P₃ receptors inhibits proliferation and anchorage-independent growth of lung adenocarcinoma cells. Mechanistically, we demonstrate that S1P₃ signaling increases epidermal growth factor receptor (EGFR) expression via the Rho kinase (ROCK) pathway in lung adenocarcinoma cells. Nuclear run-off analysis indicates that S1P/S1P₃ signaling transcriptionally increases EGFR expression. Knockdown of S1P₃ receptors diminishes the S1P-stimulated EGFR expression in lung adenocarcinoma cells. Moreover, S1P treatment greatly enhances EGF-stimulated colony formation, proliferation and invasion of lung adenocarcinoma cells. Together, these results suggest that the enhanced S1P₃-EGFR signaling axis may contribute to the tumorigenesis or progression of lung adenocarcinomas.
鞘氨醇-1-磷酸（S1P）调节广泛的生物学功能。然而，S1P 信号在肿瘤发生中的作用仍有待阐明。在这项研究中，我们表明 S1P 受体亚型 3（S1P₃）在与正常肺上皮细胞相比的肺腺癌细胞亚群中显著上调。S1P₃ 受体的特异性敲低抑制肺腺癌细胞的增殖和非锚定依赖性生长。在机制上，我们证明 S1P₃ 信号通过肺腺癌细胞中的 Rho 激酶（ROCK）通路增加表皮生长因子受体（EGFR）的表达。核流出分析表明，S1P/S1P₃ 信号通过转录增加 EGFR 的表达。S1P₃ 受体的敲低可减少 S1P 刺激的肺腺癌细胞中 EGFR 的表达。此外，S1P 处理大大增强了 EGF 刺激的肺腺癌细胞集落形成、增殖和侵袭。总之，这些结果表明增强的 S1P₃-EGFR 信号轴可能有助于肺腺癌的肿瘤发生或进展。
