Knockdown of long non-coding RNA HOTAIR increases miR-454-3p by targeting Stat3 and Atg12 to inhibit chondrosarcoma growth.
Knockdown of long non-coding RNA HOTAIR increases miR-454-3p by targeting Stat3 and Atg12 to inhibit chondrosarcoma growth.
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DOI：
10.1038/cddis.2017.31
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发表时间：
2017-02-09
影响因子：
9
通讯作者：
Guo W
中科院分区：
文献类型：
--
作者：
Bao X;Ren T;Huang Y;Sun K;Wang S;Liu K;Zheng B;Guo W
目前软骨肉瘤的治疗方法，包括宽切缘手术切除和化疗，都不能令人满意。近年来，越来越多的证据表明，长链非编码RNA（lncRNA）在肿瘤的发生和发展中起着重要作用。HOTAIR是一种典型的lncRNA，在多种肿瘤中显著过表达。然而，HOTAIR在人类软骨肉瘤中的功能和潜在的生物学机制仍不清楚。定量RT-PCR显示HOTAIR在软骨肉瘤组织和细胞系中表达上调。HOTAIR高表达与肿瘤分期及预后有关。功能实验表明，HOTAIR敲低导致体外和体内人软骨肉瘤细胞的生长抑制。除了周期停滞和细胞凋亡，HOTAIR的敲低抑制自噬，这有利于细胞死亡。从机制上讲，我们证明HOTAIR通过将EZH 2和DNMT 1募集到miR-454 - 3 p启动子区域来诱导miR-454 - 3 p的DNA甲基化，这显著沉默miR-454- 3 p表达。进一步的分析显示，STAT 3和ATG 12是miR-454- 3 p的靶点，启动HOTAIR缺陷诱导的细胞凋亡并减少自噬。总的来说，我们的数据揭示了HOTAIR在人类软骨肉瘤中的作用和功能机制，并表明HOTAIR可能作为软骨肉瘤的预后生物标志物和潜在的治疗靶点。
Current practices for the therapy of chondrosarcoma, including wide-margin surgical resection and chemotherapy, are less than satisfactory. Recently, emerging evidence has demonstrated that long non-coding RNAs (lncRNAs) have an essential role in the initiation and progression of tumors. As a typical lncRNA, HOTAIR is significantly overexpressed in various tumors. However, the function and potential biological mechanisms of HOTAIR in human chondrosarcoma remain unknown. Quantitative RT-PCR demonstrated that HOTAIR expression was upregulated in chondrosarcoma tissues and cell lines. High HOTAIR expression is correlated with tumor stage and poor prognosis. Functional experiments reveal that HOTAIR knockdown leads to growth inhibition of human chondrosarcoma cells in vitro and in vivo. In addition to cycle arrest and apoptosis, knockdown of HOTAIR inhibits autophagy, which favors cell death. Mechanistically, we demonstrated that HOTAIR induced DNA methylation of miR-454-3p by recruiting EZH2 and DNMT1 to the miR-454-3p promoter regions, which markedly silences miR-454-3p expression. Further analysis revealed that STAT3 and ATG12 are targets of miR-454-3p, initiate HOTAIR deficiency-induced apoptosis and reduce autophagy. Collectively, our data reveal the roles and functional mechanisms of HOTAIR in human chondrosarcoma and suggest that HOTAIR may act as a prognostic biomarker and potential therapeutic target for chondrosarcoma.