Functional role of gangliotetraosylceramide in epithelial-to-mesenchymal transition process induced by hypoxia and by TGF-β
Functional role of gangliotetraosylceramide in epithelial-to-mesenchymal transition process induced by hypoxia and by TGF-β
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DOI：
10.1096/fj.10-162107
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发表时间：
2010-12-01
期刊：
影响因子：
4.8
通讯作者：
Hakomori, Sen-itiroh
中科院分区：
文献类型：
--
作者：
Guan, Feng;Schaffer, Lana;Hakomori, Sen-itiroh
上皮向间充质转化(EMT)是一个基本的细胞过程，在正常胚胎发育和肿瘤进展/转移中起着关键作用。我们先前的研究表明，在转化生长因子-β诱导的小鼠和人上皮细胞的EMT过程中，神经节四糖神经酰胺(GG4)和神经节苷脂GM2明显减少，提示神经鞘糖脂(GSLS)与EMT密切相关。在本研究中，我们利用正常小鼠乳腺(NMuMG)细胞，发现在低氧(类似于1%O-2)或CoCl2(模拟低氧)诱导的EMT中，负责Gg4减少的UDP-Gal：β1-3半乳糖基转移酶-4(β3GalT4)基因的Gg4和mRNA的水平降低，与转化生长因子-β诱导的EMT相似。通过外源添加GG4或通过转染β3GalT4基因提高GG4水平可抑制缺氧诱导或转化生长因子β诱导的EMT过程，包括上皮细胞形态的改变、运动能力的增强以及与此相关的上皮与间充质分子的变化。我们还发现GG4与E-钙粘附素和β-连环素密切相关。这些结果表明，负责GG4表达的β3GalT4基因在EMT中下调；GG4在NMuMG细胞的EMT过程中具有调节功能，可能是通过与维持上皮细胞膜结构的重要上皮分子相互作用而实现的。FASE B J.24,4889-4903(2010)。Www.fasebj.org
The epithelial-to-mesenchymal transition (EMT) is a basic cellular process that plays a key role in normal embryonic development and in cancer progression/metastasis. Our previous study indicated that EMT processes of mouse and human epithelial cells induced by TGF-beta display clear reduction of gangliotetraosylceramide (Gg4) and ganglioside GM2, suggesting a close association of glycosphingolipids (GSLs) with EMT. In the present study, using normal murine mammary gland (NMuMG) cells, we found that levels of Gg4 and of mRNA for the UDP-Gal: beta 1-3galactosyltransferase-4 (beta 3GalT4) gene, responsible for reduction of Gg4, were reduced in EMT induced by hypoxia (similar to 1% O-2) or CoCl2 (hypoxia mimic), similarly to that for TGF-beta-induced EMT. An increase in the Gg4 level by its exogenous addition or by transfection of the beta 3GalT4 gene inhibited the hypoxia-induced or TGF-beta-induced EMT process, including changes in epithelial cell morphology, enhanced motility, and associated changes in epithelial vs. mesenchymal molecules. We also found that Gg4 is closely associated with E-cadherin and beta-catenin. These results suggest that the beta 3GalT4 gene, responsible for Gg4 expression, is down-regulated in EMT; and Gg4 has a regulatory function in the EMT process in NMuMG cells, possibly through interaction with epithelial molecules important to maintain epithelial cell membrane organization.-Guan, F., Schaffer, L., Handa, K., and Hakomori, S. Functional role of gangliotetraosylceramide in epithelialto-mesenchymal transition process induced by hypoxia and by TGF-beta. FASEB J. 24, 4889-4903 (2010). www.fasebj.org