Abstract：
Extracellular acidosis is a characteristic of solid tumours, resulting from hypoxia-induced glycolytic metabolism as well as from the \"Warburg effect\" (aerobic glycolysis). The acidic environment has shown to affect functional tumour properties (proliferation, migration, invasion) and thus the aim of the study was to identify signalling mechanisms, mediating these pH-dependent effects. Therefore, the serum response factor (Srf) and the activation of the serum response element (SRE) by acidosis were analysed in AT-1 prostate carcinoma cells. Furthermore, the expression of downstream targets of this cascade, namely the early growth response 1 (Egr1), which seems to be involved in tumour proliferation, and the cellular communication network factor 1 (Ccn1), which both contain SRE in their promotor region were examined in two tumour cell lines. Extracellular acidification led to an upregulation of Srf and a functional activation of the SRE. Egr1 expression was increased by acidosis in AT-1 cells whereas hypoxia had a suppressive effect. In experimental tumours, in vivo Egr1 and Ccn1 were also found to be acidosis-dependent. Also, it turned out that pH regulated expression of Egr1 was followed by comparable changes of p21, which is an important regulator of the cell cycle.This study identifies the Srf-SRE signalling cascade and downstream Egr1 and Ccn1 to be acidosis-regulated in vitro and in vivo, potentially affecting tumour progression. Especially linked expression changes of Egr1 and p21 may mediate acidosis-induced effects on cell proliferation.
摘要：
细胞外酸中毒是实体瘤的特征，由缺氧诱导的糖酵解代谢以及“Warburg效应”（有氧糖酵解）引起。酸性环境已显示影响功能性肿瘤特性(增殖，迁移,入侵)，因此研究的目的是确定信号机制，介导这些pH依赖性效应。因此,在AT-1前列腺癌细胞中分析了酸中毒引起的血清反应因子（Srf）和血清反应元件（SRE）的激活。此外，这个级联的下游目标的表达，即早期生长反应1(Egr1)，这似乎与肿瘤增殖有关，和蜂窝通信网络因子1(Ccn1)，在两种肿瘤细胞系中检查了在其启动子区域均含有SRE的细胞。细胞外酸化导致Srf的上调和SRE的功能性活化。AT-1细胞中的酸中毒增加了Egr1的表达，而缺氧具有抑制作用。在实验性肿瘤中，体内Egr1和Ccn1也被发现是酸中毒依赖性的。此外，结果表明，pH调节的Egr1表达与p21的变化相当，p21是细胞周期的重要调节因子。这项研究确定Srf-SRE信号级联和下游Egr1和Ccn1在体外和体内是酸中毒调节的，可能影响肿瘤进展。尤其是Egr1和p21的相关表达变化可能介导酸中毒对细胞增殖的影响。
