Up-regulation of MSX2 enhances the malignant phenotype and is associated with Twist 1 expression in human pancreatic cancer cells
Up-regulation of MSX2 enhances the malignant phenotype and is associated with Twist 1 expression in human pancreatic cancer cells
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DOI：
10.2353/ajpath.2008.070346
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发表时间：
2008-04-01
影响因子：
6
通讯作者：
Shimosegawa, Tooru
中科院分区：
文献类型：
--
作者：
Satoh, Kennichi;Hamada, Shin;Shimosegawa, Tooru
MSX 2被认为是器官发育的调节因子和ras信号通路的下游靶点;然而，关于MSX 2在胰腺癌发展中的作用知之甚少，其中大多数具有K-ras基因突变。因此，我们研究了MSX 2的存在是否与胰腺癌细胞的恶性行为相关。稳定过表达MSX 2的BxPC 3胰腺癌细胞表现出扁平和分散的形态，伴随着E-钙粘蛋白和β-连环蛋白从膜到细胞质的定位变化。MSX 2表达细胞的细胞增殖率、细胞迁移和非锚定依赖性细胞生长增强。与注射对照细胞相比，将MSX 2表达细胞注射到裸鼠胰腺中导致肝转移和腹膜播散显著增加。微阵列分析揭示了在表达MSX 2的细胞中Twist 1表达的显著诱导。当用MSX 2特异性小干扰RNA转染胰腺癌细胞后MSX 2失活时，Twist 1下调。人胰腺癌组织的免疫组化显示，MSX 2经常在癌细胞中表达，并且MSX 2的表达增加与较高的肿瘤分级、血管浸润和Twist I表达显著相关。这些数据表明，MSX 2通过增强Twist 1的表达诱导与上皮向间充质转化一致的变化，在胰腺癌发展中起着至关重要的作用。
MSX2 is thought to be a regulator of organ development and a downstream target of the ras signaling pathway; however, little is known about the role of MSX2 in the development of pancreatic cancers, most of which harbor a K-ras gene mutation. Therefore, we examined whether the presence of MSX2 correlates with the malignant behavior of pancreatic cancer cells. BxPC3 pancreatic cancer cells that stably overexpress MSX2 showed a flattened and scattered morphology accompanied by a change in localization of E-cadherin and beta-catenin from membrane to cytoplasm. Cell proliferation rate, cell migration, and anchorage-independent cell growth were enhanced in MSX2-expressing cells. Injection of MSX2-expressing cells into the pancreas of nude mice resulted in a significant increase in liver metastases and peritoneal disseminations compared with injection of control cells. Microarray analysis revealed a significant induction of Twist 1 expression in cells that express MSX2. When MSX2 was inactivated in pancreatic cancer cells following transfection with an MSX2-specific small interfering RNA, Twist 1 was down-regulated. Immunohistochemistry of human pancreatic carcinoma tissue revealed that MSX2 was frequently expressed in cancer cells, and that increased expression of MSX2 significantly correlated with higher tumor grade, vascular invasion, and Twist I expression. These data indicate that MSX2 plays a crucial role in pancreatic cancer development by inducing changes consistent with epithelial to mesenchymal transition through enhanced expression of Twist 1.