Cisplatin-selected resistance is associated with increased motility and stem-like properties via activation of STAT3/Snail axis in atypical teratoid/rhabdoid tumor cells.
Cisplatin-selected resistance is associated with increased motility and stem-like properties via activation of STAT3/Snail axis in atypical teratoid/rhabdoid tumor cells.
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DOI：
10.18632/oncotarget.2737
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发表时间：
2015-01-30
期刊：
影响因子：
--
通讯作者：
Ma HI
中科院分区：
文献类型：
--
作者：
Liu WH;Chen MT;Wang ML;Lee YY;Chiou GY;Chien CS;Huang PI;Chen YW;Huang MC;Chiou SH;Shih YH;Ma HI
非典型畸胎样/横纹肌样肿瘤（ATRT）是一种小儿脑恶性肿瘤，在完全手术和化疗后复发率很高。在这里，我们证明顺铂治疗不仅选择耐药，但也为一个更致癌的表型，其特点是高自我更新和侵入能力。这些现象可能是由于STAT 3上调，这与ATRT-CisR细胞中上皮-间充质转化（EMT）的激活剂Snail的较高表达同时发生。STAT 3敲低有效地抑制了Snail的表达，并阻断了ATRT-CisR细胞的运动性和侵袭性，而过表达Snail则逆转了这些作用。染色质免疫沉淀实验表明STAT 3与Snail启动子直接结合。此外，STAT 3敲低有效地抑制了癌干细胞样特性，协同增强了化疗效果，并显着提高了ATRT-CisR移植免疫功能低下小鼠的存活率。最后，免疫组化分析显示STAT 3和Snail在复发性ATRT组织中呈高水平共表达。因此，STAT 3/Snail通路在致癌耐药性中起着重要作用，使细胞不仅具有耐药性，而且越来越致癌（侵袭，EMT和复发）。因此，STAT 3/Snail可能是ATRT治疗的靶点。
Atypical teratoid/rhabdoid tumor (ATRT) is a malignant pediatric brain tumor with great recurrence after complete surgery and chemotherapy. Here, we demonstrate that cisplatin treatment selects not only for resistance but also for a more oncogenic phenotype characterized by high self-renewal and invasive capabilities. These phenomena are likely due to STAT3 upregulatoin which occurred simultaneously with higher expression of Snail, an activator of epithelial–mesenchymal transition (EMT), in ATRT-CisR cells. STAT3 knockdown effectively suppressed Snail expression and blocked motility and invasion in ATRT-CisR cells, while overexpressing Snail reversed these effects. Chromatin immunoprecipitation assay indicated that STAT3 directly bound to Snail promoter. Moreover, STAT3 knockdown effectively suppressed cancer stem-like properties, synergistically enhanced the chemotherapeutic effect, and significantly improved survival rate in ATRT-CisR-transplanted immunocompromised mice. Finally, immunohistochemistrical analysis showed that STAT3 and Snail were coexpressed at high levels in recurrent ATRT tissues. Thus, the STAT3/Snail pathway plays an important role in oncogenic resistance, rendering cells not only drug-resistant but also increasingly oncogenic (invasion, EMT and recurrence). Therefore, the STAT3/Snail could be a target for ATRT treatment.
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影响因子：
3.8
作者：
Haslehurst AM;Koti M;Dharsee M;Nuin P;Evans K;Geraci J;Childs T;Chen J;Li J;Weberpals J;Davey S;Squire J;Park PC;Feilotter H
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25.7
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影响因子：
5.6
作者：
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通讯作者：
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