上皮-間質(zhì)轉(zhuǎn)化（epithelial mesenchymal transitions，EMT）是指上皮細(xì)胞在形態(tài)學(xué)上發(fā)生向成纖維細(xì)胞或間充質(zhì)細(xì)胞表型的轉(zhuǎn)變并獲得遷移的能力,。EMT是胚胎發(fā)育中的一個(gè)基本過程,，它使在特殊部位產(chǎn)生的上皮細(xì)胞從上皮組織分離并遷移到其他位置，是正常發(fā)育,、傷口愈合以及惡性上皮腫瘤發(fā)生的基礎(chǔ),。
腫瘤浸潤和轉(zhuǎn)移是癌癥死亡的最常見的原因。上皮型腫瘤細(xì)胞侵入周圍組發(fā)生轉(zhuǎn)移,，其中上皮間質(zhì)轉(zhuǎn)化是必需的,。近日，發(fā)表在PLoS On雜志上的一則研究證明FGFR1在膀胱癌中的表達(dá)是增加的,，F(xiàn)GFR1的激活誘導(dǎo)上皮癌（UC）細(xì)胞株發(fā)生EMT,。
研究人員在體外創(chuàng)建了FGFR1誘導(dǎo)的EMT模型，并用這個(gè)模型來研究尿路上皮腫瘤的EMT過程,。FGFR1的激活促進(jìn)了72小時(shí)內(nèi)的EMT,。最初肌動(dòng)蛋白應(yīng)力纖維出現(xiàn)快速增長，細(xì)胞大小增加,，腫瘤細(xì)胞形態(tài)發(fā)生改變,，遷移和侵襲增加。
通過定點(diǎn)突變和小分子抑制劑證明，有絲分裂原活化蛋白激酶（MAPK）和磷脂酶C伽瑪（PLCγ）途徑調(diào)節(jié)EMT過程,。肌動(dòng)蛋白應(yīng)力纖維的形成受PLCγ激活,，對細(xì)胞大小增加，遷移和改變形態(tài)非常重要,。MAPK的活化調(diào)控遷移和E-cadherin表達(dá),，表明PLCγ和MAPK的聯(lián)合激活對一個(gè)完整的EMT是需要的。
接下來,，研究者采用芯片微列陳評估這些信號(hào)級(jí)聯(lián)的下游基因表達(dá)的變化,。發(fā)現(xiàn)FGFR1上調(diào)COX-2，造成細(xì)胞內(nèi)前列腺素E（2）水平的增加,，促進(jìn)遷移,。總之,，研究數(shù)據(jù)證明,，在上皮癌（UC）細(xì)胞株中，F(xiàn)GFR1的激活通過協(xié)調(diào)多個(gè)信號(hào)通路的激活,，促進(jìn)前列腺素合成激活,，促進(jìn)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.
