Lu Zhaoyang, Wang Jiabei, Zheng Tongsen, Liang Yingjian, Yin Dalong, Song Ruipeng, Pei Tiemin, Pan Shangha, Jiang Hongchi, Liu Lianxin
Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Key Laboratory of Hepatosplenic Surgery, Ministry of Education, No, 23 Youzheng Street, Heilongjiang Province, Harbin 150001, China.
BMC Cancer. 2014 Oct 25;14:783. doi: 10.1186/1471-2407-14-783.
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.
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存在，导致髓样细胞白血病1（Mcl-1）表达增强和细胞凋亡抗性。新型免疫抑制剂FTY720源自ISP-1，其潜在抗癌特性已得到研究。本研究旨在阐明FTY720介导胆管癌（CC）细胞抗肿瘤作用的机制。
检测了三种CC细胞系，QBC939、TFK-1和HuCCT1。在体外和体内评估了FTY720的治疗效果。检测了细胞增殖、凋亡、细胞周期、侵袭潜能和上皮-间质转化（EMT）。
FTY720在体外和体内均能显著抑制CC细胞增殖和EMT，且该效应与STAT3tyr705去磷酸化有关。FTY720诱导CC细胞凋亡和G1期阻滞，并抑制CC细胞侵袭。蛋白质免疫印迹分析表明，FTY720以剂量依赖性方式诱导半胱天冬酶3、8和9以及聚（ADP-核糖）聚合酶（PARP）的裂解，这与p-STAT3、Bcl-xL、Bcl-2、生存素、细胞周期蛋白D1、细胞周期蛋白E、N-钙黏蛋白、波形蛋白（vimentin）、血管内皮生长因子（VEGF）和TWIST1的显著减少一致。体内研究表明，FTY720治疗后肿瘤生长和转移受到显著抑制。
这些结果表明，FTY720可使p-STAT3显著降低，从而抑制CC细胞增殖和EMT，进而诱导G1期阻滞和细胞凋亡。我们鉴定了一种新型免疫抑制剂，其通过抑制p-STAT3对CC显示出潜在的抗肿瘤作用。FTY720值得进一步研究并进行临床评估。
