Department of Pharmacology, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway.
Biochem Biophys Res Commun. 2012 May 4;421(2):255-60. doi: 10.1016/j.bbrc.2012.03.148. Epub 2012 Apr 6.
Prostaglandin E(2) (PGE(2)) enhances the mitogenic response to epidermal growth factor (EGF) in hepatocytes, but the underlying mechanisms are not clear. We previously observed that PGE(2) upregulates EGF-induced signalling in the MEK/ERK and PI3K/Akt pathways in hepatocytes. Other investigations have indicated that ErbB2 enhances the mitogenic effect of EGF in these cells. In the present study we found that treatment with PGE(2) increased ErbB2 and decreased ErbB3 expression at both the mRNA and protein level in cultured rat hepatocytes. Silencing of the ErbB2 expression with specific siRNA blocked the stimulation by PGE(2) and EGF of cyclin D1 expression and DNA synthesis. Both EGF and PGE(2) increased the expression of ERK and Akt, but while the effect of EGF was inhibited by ErbB2-directed siRNA, this did not affect the PGE(2)-induced upregulation of ERK and Akt. These data suggest that PGE(2) can enhance the mitogenic effect of EGF both by increasing ErbB2 expression and by ErbB2-independent mechanisms.
前列腺素 E（2）（PGE（2））增强了肝细胞对表皮生长因子（EGF）的有丝分裂反应，但潜在的机制尚不清楚。我们之前观察到 PGE（2）上调了肝细胞中 MEK/ERK 和 PI3K/Akt 途径中 EGF 诱导的信号。其他研究表明，ErbB2 增强了这些细胞中 EGF 的有丝分裂作用。在本研究中，我们发现 PGE（2）处理在培养的大鼠肝细胞中同时增加了 ErbB2 mRNA 和蛋白水平，并降低了 ErbB3 的表达。用特异性 siRNA 沉默 ErbB2 的表达阻断了 PGE（2）和 EGF 对细胞周期蛋白 D1 表达和 DNA 合成的刺激。EGF 和 PGE（2）均增加了 ERK 和 Akt 的表达，但 EGF 的作用被 ErbB2 定向 siRNA 抑制，而这并不影响 PGE（2）诱导的 ERK 和 Akt 的上调。这些数据表明，PGE（2）可以通过增加 ErbB2 表达和 ErbB2 非依赖性机制来增强 EGF 的有丝分裂作用。
