Epithelial-mesenchymal transition is a critical step in tumorgenesis of pancreatic neuroendocrine tumors.
Epithelial-mesenchymal transition is a critical step in tumorgenesis of pancreatic neuroendocrine tumors.
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DOI：
10.3390/cancers4010281
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发表时间：
2012-03-08
期刊：
影响因子：
5.2
通讯作者：
Konig, Alexander
中科院分区：
文献类型：
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作者：
Fendrich, Volker;Maschuw, Katja;Konig, Alexander
转录因子Snail， Slug和Twist抑制E-cadherin并诱导上皮-间质转化（EMT），这是侵袭性癌细胞利用的一个过程。在这项研究中，我们评估了EMT在胰腺神经内分泌肿瘤（PNETs）的体外、体内和人体肿瘤标本中的作用。采用免疫组织化学和实时PCR分析EMT标志物的表达。在体外研究中，我们分析了用siRNA转染鼻涕虫或蜗牛前后BON-1细胞EMT标记物的表达情况，并进行了细胞聚集分析。为了评估体内效应，从5-10周龄开始，给Rip1Tag2小鼠注射了载药或蜗牛抑制剂polythlylenglykol。用重量、肿瘤细胞增殖和凋亡评价切除胰腺。Snail和Twist分别在61%和64%的PNETs中表达。这与e -钙粘蛋白的缺失有关。RT-PCR结果显示，EMT标记Slug和Snail在BON-1细胞中均有保存。用siRNA转染Slug与E-cadherin上调，增强细胞间粘附和抑制细胞增殖有关。在Rip1Tag2小鼠体内，PEG对蜗牛的抑制作用与细胞凋亡增加、肿瘤细胞增殖减少和肿瘤体积显著减小有关。目前的数据表明，EMT在PNETs的肿瘤发生中起关键作用。蜗牛在人类PNETs中相当一部分的激活以及PEG对蜗牛在转基因小鼠胰岛细胞肿瘤中的成功抑制作用为蜗牛作为PNETs中的药物靶点提供了第一个证据。
The transcription factors Snail, Slug and Twist repress E-cadherin and induce epithelial-mesenchymal transition (EMT), a process exploited by invasive cancer cells. In this study, we evaluated the role of EMT in the tumorgenesis of neuroendocrine tumors of the pancreas (PNETs) in vitro, in vivo and human tumor specimen. Expression of EMT markers was analyzed using immunohistochemistry and real-time PCR. For in vitro studies, BON-1 cells were analyzed regarding expression of EMT markers before and after transfection with siRNA against Slug or Snail, and cell aggregation assays were performed. To asses in vivo effects, Rip1Tag2 mice were treated with vehicle or the snail-inhibitor polythlylenglykol from week 5-10 of age. The resected pancreata were evaluated by weight, tumor cell proliferation and apoptosis. Snail and Twist was expressed in 61 % and 64% of PNETs. This was associated with loss of E-cadherin. RT-PCR revealed conservation of the EMT markers Slug and Snail in BON-1 cells. Transfection with siRNA against Slug was associated with upregulation of E-cadherin, enhanced cell-cell adhesion and inhibition of cell proliferation. Snail-inhibition in vivo by PEG was associated with increased apoptosis, decreased tumor cell proliferation and dramatic reduced tumor volume in Rip1Tag2 mice. The presented data show that EMT plays a key role in tumorgenesis of PNETs. The activation of Snail in a considerable subset of human PNETs and the successful effect of Snail inhibition by PEG in islet cell tumors of transgenic mice provides first evidence of Snail as a drug target in PNETs.