Expression of the calcium-binding protein S100P is regulated by bone morphogenetic protein in pancreatic duct epithelial cell lines
Expression of the calcium-binding protein S100P is regulated by bone morphogenetic protein in pancreatic duct epithelial cell lines
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DOI：
10.1111/j.1349-7006.2008.00993.x
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发表时间：
2009-01-01
期刊：
影响因子：
5.7
通讯作者：
Shimosegawa, Tooru
中科院分区：
文献类型：
--
作者：
Hamada, Shin;Satoh, Kennichi;Shimosegawa, Tooru
我们先前报道了骨形态发生蛋白（BMP）-4诱导胰腺癌细胞系上皮间质转化。为了进一步研究BMP在胰腺癌中作用的详细分子机制，我们在Panc-1细胞中进行了全面的微阵列分析。微阵列分析阐明了新的BMP靶基因，其中，钙结合蛋白S100 P被鉴定为上调基因。在Panc-1和HPDE细胞中，通过实时逆转录聚合酶链反应和蛋白质印迹分析证实了BMP 4对S100 P的诱导。基于短干扰RNA的S100 P表达敲低足以抑制Panc-1细胞中BMP 4诱导的细胞迁移。由于Panc-1和HPDE细胞表达野生型Smad 4，我们假设Smad 4可能是BMP 4诱导S100 P所不可或缺的。在Smad 4-null细胞系BxPC 3中没有观察到BMP 4对S100 P的诱导，并且在基于短干扰RNA的Smad 4敲低Panc-1细胞中充分减弱。有趣的是，详细的启动子分析显示，BMP 4上调S100 P是独立的Smad结合元件，这表明一个额外的未知的下游因素的Smad 4依赖性途径是必要的，这种诱导。这些发现是同类研究中的第一个，BMP信号对S100 P的这种Smad 4依赖性调节可能解释了癌细胞的迁移机制，这仍然是未知的。（Cancer Sci 2009; 100：103-110）。
We previously reported that bone morphogenetic protein (BMP)-4 induces epithelial-mesenchymal transition in a pancreatic cancer cell line. To further investigate the detailed molecular mechanism of BMP action in pancreatic cancer, we carried out comprehensive microarray analysis in Panc-1 cells. The microarray analysis elucidated novel BMP target genes, and among them, the calcium-binding protein S100P was identified as an upregulated gene. S100P induction by BMP4 was confirmed by real-time reverse transcription-polymerase chain reaction and western blot analysis in Panc-1 and HPDE cells. Short interfering RNA-based knockdown of S100P expression sufficiently repressed BMP4-induced cell migration in Panc-1 cells. Because Panc-1 and HPDE cells express wild-type Smad4, we hypothesized that Smad4 might be indispensable for S100P induction by BMP4. S100P induction by BMP4 was not observed in the Smad4-null cell line BxPC3, and was sufficiently attenuated in short interfering RNA-based Smad4-knockdown Panc-1 cells. Interestingly, detailed promoter analysis revealed that upregulation of S100P by BMP4 was independent of the Smad-binding element, indicating that an additional unknown downstream factor of the Smad4-dependent pathway is necessary for this induction. These findings are the first of their kind, and this Smad4-dependent regulation of S100P by BMP signaling might explain the migratory mechanism of cancer cells, which is still unknown. (Cancer Sci 2009; 100: 103-110).