FTY720 inhibits proliferation and epithelial-mesenchymal transition in cholangiocarcinoma by inactivating STAT3 signaling.
FTY720 inhibits proliferation and epithelial-mesenchymal transition in cholangiocarcinoma by inactivating STAT3 signaling.
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FTY720 通过灭活 STAT3 信号传导来抑制胆管癌的增殖和上皮间质转化。
DOI：
10.1186/1471-2407-14-783
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发表时间：
2014-10-25
期刊：
影响因子：
3.8
通讯作者：
Liu L
中科院分区：
文献类型：
--
作者：
Lu Z;Wang J;Zheng T;Liang Y;Yin D;Song R;Pei T;Pan S;Jiang H;Liu L
白细胞介素6 （IL-6）介导的信号转导和转录激活因子3 （STAT-3）磷酸化（激活）在胆管癌细胞中异常持续，导致髓细胞白血病1 （Mcl-1）表达增强和对凋亡的抵抗。FTY720是一种新的免疫抑制剂，由ISP-1衍生而来，研究其可能的抗癌特性。本研究旨在阐明FTY720介导胆管癌（CC）细胞抗肿瘤作用的机制。检测三种CC细胞系QBC939、TFK-1和HuCCT1。体外、体内评价FTY720的治疗效果。检测细胞增殖、凋亡、细胞周期、侵袭电位和上皮-间质转化（EMT）。FTY720在体外和体内均能显著抑制CC细胞的增殖和EMT，这种作用与STAT3tyr705的去磷酸化有关。FTY720诱导CC细胞凋亡和G1期阻滞，抑制CC细胞侵袭。Western blot分析显示，FTY720诱导caspases 3、8、9和PARP的断裂呈剂量依赖性，与p-STAT3、Bcl-xL、Bcl-2、survivin、cyclin D1、cyclin E、N-cadherin、vimentin、VEGF和TWIST1的显著降低一致。体内研究表明，FTY720治疗后，肿瘤生长和转移明显受到抑制。这些结果表明，FTY720诱导p-STAT3显著降低，抑制CC细胞的增殖和EMT，进而诱导G1期阻滞和凋亡。我们已经鉴定了一种新的免疫抑制剂，它通过抑制p-STAT3对CC有潜在的抗肿瘤作用。FTY720值得进一步研究和临床评估。本文的在线版本（doi:10.1186/1471-2407-14-783）包含补充材料，可供授权用户使用。
Interleukin 6 (IL-6)-mediated signal transducers and activators of transcription 3 (STAT-3) phosphorylation (activation) is aberrantly sustained in cholangiocarcinoma cells resulting in enhanced myeloid cell leukemia 1 (Mcl-1) expression and resistance to apoptosis. FTY720, a new immunosuppressant, derived from ISP-1, has been studied for its putative anti-cancer properties. This study aimed to elucidate the mechanism by which FTY720 mediates antitumor effects in cholangiocarcinoma (CC) cells. Three CC cell lines were examined, QBC939, TFK-1, and HuCCT1. The therapeutic effects of FTY720 were evaluated in vitro and in vivo. Cell proliferation, apoptosis, cell cycle, invasive potential, and epithelial- mesenchy-mal transition (EMT) were examined. FTY720 greatly inhibited CC cells proliferation and EMT in vitro and in vivo, and this effect was associated with dephosphorylation of STAT3tyr705. FTY720 induced apoptosis and G1 phase arrest in CC cells, and inhibited invasion of CC cells. Western blot analysis showed that FTY720 induced cleavage of caspases 3, 8 and 9, and of PARP, in a dose-dependent manner, consistent with a substantial decrease in p-STAT3, Bcl-xL, Bcl-2, survivin, cyclin D1, cyclin E, N-cadherin, vimentin, VEGF and TWIST1. In vivo studies showed that tumor growth and metastasis were significantly suppressed after FTY720 treatment. These results suggest that FTY720 induces a significant decrease in p-STAT3, which inhibits proliferation and EMT of CC cells, and then induces G1 phase arrest and apoptosis. We have characterized a novel immunosuppressant, which shows potential anti-tumor effects on CC via p-STAT3 inhibition. FTY720 merits further investigation and warrants clinical evaluation. The online version of this article (doi:10.1186/1471-2407-14-783) contains supplementary material, which is available to authorized users.
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影响因子：
4.7
作者：
Dunn, L. L.;Sekyere, E. O.;Richardson, D. R.
通讯作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.0603507103
发表时间：
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影响因子：
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影响因子：
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