上皮-间质转化（epithelial mesenchymal transitions，EMT）是指上皮细胞在形态学上发生向成纤维细胞或间充质细胞表型的转变并获得迁移的能力。EMT是胚胎发育中的一个基本过程，它使在特殊部位产生的上皮细胞从上皮组织分离并迁移到其他位置，是正常发育、伤口愈合以及恶性上皮肿瘤发生的基础。
肿瘤浸润和转移是癌症死亡的最常见的原因。上皮型肿瘤细胞侵入周围组发生转移，其中上皮间质转化是必需的。近日，发表在PLoS On杂志上的一则研究证明FGFR1在膀胱癌中的表达是增加的，FGFR1的激活诱导上皮癌（UC）细胞株发生EMT。
研究人员在体外创建了FGFR1诱导的EMT模型，并用这个模型来研究尿路上皮肿瘤的EMT过程。FGFR1的激活促进了72小时内的EMT。最初肌动蛋白应力纤维出现快速增长，细胞大小增加，肿瘤细胞形态发生改变，迁移和侵袭增加。
通过定点突变和小分子抑制剂证明，有丝分裂原活化蛋白激酶（MAPK）和磷脂酶C伽玛（PLCγ）途径调节EMT过程。肌动蛋白应力纤维的形成受PLCγ激活，对细胞大小增加，迁移和改变形态非常重要。MAPK的活化调控迁移和E-cadherin表达，表明PLCγ和MAPK的联合激活对一个完整的EMT是需要的。
接下来，研究者采用芯片微列陈评估这些信号级联的下游基因表达的变化。发现FGFR1上调COX-2，造成细胞内前列腺素E（2）水平的增加，促进迁移。总之，研究数据证明，在上皮癌（UC）细胞株中，FGFR1的激活通过协调多个信号通路的激活，促进前列腺素合成激活，促进EMT。（生物谷：Bioon.com）
doi:10.1371/journal.pone.0038972
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FGFR1-Induced Epithelial to Mesenchymal Transition through MAPK/PLCγ/COX-2-Mediated Mechanisms
Darren C. Tomlinson,1 Euan W. Baxter,1 Paul M. Loadman,2 Mark A. Hull,3 and Margaret A. Knowles1,*
Tumour invasion and metastasis is the most common cause of death from cancer. For epithelial cells to invade surrounding tissues and metastasise, an epithelial-mesenchymal transition (EMT) is required. We have demonstrated that FGFR1 expression is increased in bladder cancer and that activation of FGFR1 induces an EMT in urothelial carcinoma (UC) cell lines. Here, we created an in vitro FGFR1-inducible model of EMT, and used this model to identify regulators of urothelial EMT. FGFR1 activation promoted EMT over a period of 72 hours. Initially a rapid increase in actin stress fibres occurred, followed by an increase in cell size, altered morphology and increased migration and invasion. By using site-directed mutagenesis and small molecule inhibitors we demonstrated that combined activation of the mitogen activated protein kinase (MAPK) and phospholipase C gamma (PLCγ) pathways regulated this EMT. Actin stress fibre formation was regulated by PLCγ activation, and was also important for the increase in cell size, migration and altered morphology. MAPK activation regulated migration and E-cadherin expression, indicating that combined activation of PLCγand MAPK is required for a full EMT. We used expression microarrays to assess changes in gene expression downstream of these signalling cascades. COX-2 was transcriptionally upregulated by FGFR1 and caused increased intracellular prostaglandin E2 levels, which promoted migration. In conclusion, we have demonstrated that FGFR1 activation in UC cells lines promotes EMT via coordinated activation of multiple signalling pathways and by promoting activation of prostaglandin synthesis.
