Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 30013, Taiwan, ROC.
Institute of Biotechnology, National Tsing Hua University, Hsinchu 30013, Taiwan, ROC; Department of Life Science, National Tsing Hua University, Hsinchu, 30013, Taiwan, ROC.
Biochim Biophys Acta Mol Cell Res. 2019 Mar;1866(3):486-503. doi: 10.1016/j.bbamcr.2018.10.011. Epub 2018 Oct 13.
Protease-activated receptor 2 (PAR2), a G protein-coupled receptor for trypsin, contributes to growth, anti-apoptosis, and migration in lung cancer. Given that PAR2 activation in airway epithelial cells compromises the airway epithelium barrier by disruption of E-cadherin adhesion, PAR2 may be involved in epithelial-mesenchymal transition (EMT) in lung adenocarcinoma cells. Although PAR2 is known to promote the migration of lung cancer cells, the detailed mechanism of this event is still not clear. Here, we found that PAR2 is highly expressed in several lung adenocarcinoma cell lines. In two lung adenocarcinoma cell lines, CL1-5 and H1299 cells, activation of PAR2 induces migration and Slug-mediated EMT. The underlying mechanisms involved in PAR2-induced migration and EMT in CL1-5 cells were further investigated. We showed that PAR2-induced migration of CL1-5 cells is mediated by the Src/p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway. β-arrestin 1, not G protein, is involved in this PAR2-mediated Src/p38 MAPK signaling pathway. PAR2-induced EMT in CL1-5 cells is dependent on the activation of extracellular-signal-regulated kinase 2 (ERK2). The activation of ERK2 further mediates Slug stabilization through suppressing the activity of glycogen synthase kinase 3β. In addition, a poor prognosis was observed in lung adenocarcinoma patients with a high expression of PAR2. Thus, PAR2 regulates migration through β-arrestin 1-dependent activation of p38 MAPK and EMT through ERK2-mediated stabilization of Slug in lung adenocarcinoma cells. Our finding also suggests that PAR2 might serve as a therapeutic target for metastatic lung adenocarcinoma and a potential biomarker for predicting the prognosis of lung adenocarcinoma.
蛋白酶激活受体 2（PAR2）是一种丝氨酸蛋白酶的 G 蛋白偶联受体，它促进肺癌的生长、抗凋亡和迁移。鉴于气道上皮细胞中 PAR2 的激活通过破坏 E-钙黏蛋白黏附来破坏气道上皮屏障，PAR2 可能参与肺腺癌细胞中的上皮-间充质转化（EMT）。尽管已知 PAR2 可促进肺癌细胞的迁移，但该事件的详细机制仍不清楚。在这里，我们发现 PAR2 在几种肺腺癌细胞系中高表达。在两种肺腺癌细胞系 CL1-5 和 H1299 中，PAR2 的激活诱导迁移和 Slug 介导的 EMT。进一步研究了 PAR2 在 CL1-5 细胞中诱导迁移和 EMT 的潜在机制。我们表明，PAR2 诱导 CL1-5 细胞迁移是由Src/p38 丝裂原活化蛋白激酶（p38 MAPK）信号通路介导的。β-arrestin 1 而不是 G 蛋白参与此 PAR2 介导的 Src/p38 MAPK 信号通路。PAR2 在 CL1-5 细胞中诱导的 EMT 依赖于细胞外信号调节激酶 2（ERK2）的激活。ERK2 的激活进一步通过抑制糖原合酶激酶 3β的活性来介导 Slug 的稳定。此外，在 PAR2 高表达的肺腺癌患者中观察到预后不良。因此，PAR2 通过β-arrestin 1 依赖性激活 p38 MAPK 调节迁移，并通过 ERK2 介导的 Slug 稳定来调节 EMT 在肺腺癌细胞中。我们的发现还表明，PAR2 可能成为转移性肺腺癌的治疗靶点，并可能成为预测肺腺癌预后的潜在生物标志物。
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