Chemoresistance to paclitaxel induces epithelial-mesenchymal transition and enhances metastatic potential for epithelial ovarian carcinoma cells.
Chemoresistance to paclitaxel induces epithelial-mesenchymal transition and enhances metastatic potential for epithelial ovarian carcinoma cells.
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DOI：
10.3892/ijo.31.2.277
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发表时间：
2007-08
影响因子：
5.2
通讯作者：
H. Kajiyama;K. Shibata;Mikio Terauchi;Mamoru Yamashita;K. Ino;A. Nawa;F. Kikkawa
中科院分区：
文献类型：
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作者：
H. Kajiyama;K. Shibata;Mikio Terauchi;Mamoru Yamashita;K. Ino;A. Nawa;F. Kikkawa
本研究的目的是评估紫杉醇耐药上皮性卵巢癌（EOC）细胞的细胞形态，运动性和分子变化与上皮间质转化（EMT）一致。将人EOC细胞系NOS-2、TAOV和SKOV-3连续暴露于增加剂量的紫杉醇以建立三种稳定的紫杉醇抗性细胞系（分别为NOS-PR、TAOV-PR和SKOV-PR细胞）。使用这些细胞系，细胞功能，如运动性，侵袭能力和增殖潜力进行了评估。使用Western印迹分析评估了参与EMT或细胞侵袭的几种分子。在腹腔转移模型中，我们使用NOS-2或NOS-PR细胞接种小鼠，研究腹膜扩散和生存时间的差异。NOS 2-PR细胞表现出与EMT一致的表型变化;具有梭形形态和增强的伪足形成。Western blot分析显示，与NOS-2细胞相比，NOS-PR细胞中上皮粘附分子E-cadherin的表达降低，间充质标志物如波形蛋白、纤连蛋白和平滑肌肌动蛋白的表达增加。NOS 2-PR细胞显示EMT调节转录因子Snail和Twist表达增加。与NOS-2细胞相比，NOS-2-PR细胞在创伤试验中的迁移潜力和向小鼠腹膜的转移潜力显著增强。这些数据表明，有一个可能的联系之间的慢性紫杉醇耐药性和诱导EMT的EOC细胞。通过进一步了解化疗耐药性和EMT的机制，可能会使治疗获益，如恢复化疗敏感性或抑制转移。
The aim of this study was to assess paclitaxel resistant-epithelial ovarian carcinoma (EOC) cells for cellular morphology, motility, and molecular changes consistent with epithelial-mesenchymal transition (EMT). The human EOC cell lines NOS-2, TAOV and SKOV-3 were continuously exposed to increasing doses of paclitaxel to establish three stable cell lines resistant to paclitaxel (NOS-PR, TAOV-PR, and SKOV-PR cells, respectively). Using these cell lines, cellular functions such as motility, invasive ability, and proliferative potential were assessed. Several molecules involved in EMT or cell invasiveness were assessed using Western blot analysis. In a peritoneal metastasis model using mice inoculated with NOS-2 or NOS-PR cells, we investigated the differences of peritoneal dissemination and survival time. NOS2-PR cells showed phenotypic changes consistent with EMT; with spindle-shaped morphology and enhanced pseudopodia formation. Western blot analysis revealed decreased expression of the epithelial adhesion molecule, E-cadherin and an increase in mesenchymal markers such as vimentin, fibronectin and smooth-muscle actin in NOS-PR cells compared to NOS-2 cells. The NOS2-PR cells displayed increased expression of Snail and Twist, EMT-regulatory transcription factors. Migratory potential in a wound assay and metastatic potential to the peritoneum of mice were markedly enhanced in NOS2-PR cells compared to NOS-2 cells. These data suggest that there is a possible link between chronic paclitaxel-resistance and induction of the EMT in EOC cells. It is possible that therapeutic benefits such as the restoration of chemosensitivity or suppression of metastasis will be enabled by gaining further insight into the mechanisms underlying chemoresistance and EMT.