Msx2 induces epithelial-mesenchymal transition in mouse mammary epithelial cells through upregulation of Cripto-1.
Msx2 induces epithelial-mesenchymal transition in mouse mammary epithelial cells through upregulation of Cripto-1.
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DOI：
10.1002/jcp.21712
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发表时间：
2009-06
影响因子：
5.6
通讯作者：
Vonderhaar, B. K.
中科院分区：
文献类型：
--
作者：
Di Bari, M. G.;Ginsburg, E.;Plant, J.;Strizzi, L.;Salomon, D. S.;Vonderhaar, B. K.
上皮间质转化（EMT）是胚胎发生和浸润性癌症早期阶段发生的过程。经历 EMT 的上皮细胞变得更具迁移性和侵袭性，具有间充质形态。在此，我们评估了由 Msx2 驱动的小鼠乳腺上皮细胞系中 EMT 的诱导，Msx2 是一种在乳腺发育过程中重要的含有同源盒的转录因子。 NMuMG 细胞（一种正常小鼠乳腺上皮细胞系）稳定转染 Msx2 cDNA，显示上皮标记物 E-钙粘蛋白下调，间质标记物波形蛋白和 N-钙粘蛋白上调。此外，在 Msx2 转染的细胞中检测到 Cripto-1 的过度表达，Cripto-1 是已知参与 EMT 的表皮生长因子-CFC 蛋白家族的成员。 Cripto-1的表达伴随着酪氨酸激酶c-Src通路的激活和细胞侵袭能力的增加。功能测定还证明 c-Src 特异性抑制剂可抑制 Msx2 转染细胞的侵袭行为。此外，人浸润性乳腺癌的免疫组织化学显示，仅在浸润性肿瘤细胞中Msx2染色呈阳性，而非浸润性肿瘤细胞呈阴性。这些结果表明，Msx2 可能在促进上皮细胞的 EMT 过程中发挥重要作用，而上皮细胞获得与肿瘤侵袭相关的特性。
Epithelial-Mesenchymal Transition (EMT) is a process occurring during both embryogenesis and early stages of invasive cancer. Epithelial cells that undergo EMT become more migratory and invasive with a mesenchymal morphology. Herein we assess EMT induction in a mouse mammary epithelial cell line driven by Msx2, a homeobox-containing transcription factor important during mammary gland development. NMuMG cells, a normal mouse mammary epithelial cell line, stably-transfected with a Msx2 cDNA showed downregulation of an epithelial marker E-cadherin and upregulation of the mesenchymal markers vimentin and N-cadherin. Furthermore, overexpression of Cripto-1, a member of the epidermal growth factor-CFC protein family already known to be involved in EMT, was detected in Msx2-transfected cells. The expression of Cripto-1 was accompanied by activation of the tyrosine kinase c-Src pathway and an increase in the invasive ability of the cells. Functional assays also demonstrated inhibition of the invasive behavior of the Msx2-transfected cells by a c-Src specific inhibitor. Moreover, immunohistochemistry of human infiltrating breast carcinomas showed positive staining for Msx2 only in the infiltrating tumor cells while the non-infiltrating tumor cells were negative. These results suggest that Msx2 may play a significant role in promoting EMT in epithelial cells that acquire properties involved in tumor invasion.
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