Telomerase reverse transcriptase promotes epithelial-mesenchymal transition and stem cell-like traits in cancer cells
Telomerase reverse transcriptase promotes epithelial-mesenchymal transition and stem cell-like traits in cancer cells
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DOI：
10.1038/onc.2012.441
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发表时间：
2013-09-05
期刊：
影响因子：
8
通讯作者：
Xu, D.
中科院分区：
文献类型：
--
作者：
Liu, Z.;Li, Q.;Xu, D.
通过诱导端粒酶逆转录酶（hTERT）激活端粒酶有助于稳定端粒的恶性转化。临床研究表明，较高的hTERT表达与癌症进展和不良预后相关，但其潜在机制尚不清楚。由于上皮-间充质转化（EMT）和癌症干细胞（CSCs）是癌症转移和复发的关键因素，并且hTERT已被证明具有独立于其端粒延长功能的多种生物活性，因此我们以胃癌（GC）为模型探讨了hTERT在EMT和CSCs中的潜在作用。hTERT过表达分别促进GC细胞的EMT和干性，而抑制hTERT过表达则抑制其干性。转化生长因子(TGF)- β 1和β -连环蛋白介导的EMT被hTERT表达的小干扰RNA清除。hTERT与β -catenin相互作用，增强其核定位和转录活性，占据β -catenin靶蛋白vimentin启动子。所有这些hTERT的作用都独立于其端粒延长功能或端粒酶活性。在GC样品中，hTERT和EMT标记物的表达呈正相关。小鼠实验证明了hTERT对癌细胞定植的体内刺激作用。总的来说，hTERT刺激EMT，诱导癌细胞的干细胞，从而促进癌症的转移和复发。因此，靶向hTERT可能通过抑制EMT和csc来阻止癌症进展。
Telomerase activation through induction of telomerase reverse transcriptase (hTERT) contributes to malignant transformation by stabilizing telomeres. Clinical studies demonstrate that higher hTERT expression is associated with cancer progression and poor outcomes, but the underlying mechanism is unclear. Because epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) are key factors in cancer metastasis and relapse, and hTERT has been shown to exhibit multiple biological activities independently of its telomere-lengthening function, we address a potential role of hTERT in EMT and CSCs using gastric cancer (GC) as a model. hTERT overexpression promotes, whereas its inhibition suppresses, EMT and stemness of GC cells, respectively. Transforming growth factor (TGF)-beta 1 and beta-catenin-mediated EMT was abolished by small interfering RNA depletion of hTERT expression. hTERT interacts with beta-catenin, enhances its nuclear localization and transcriptional activity, and occupies the beta-catenin target vimentin promoter. All these hTERT effects were independent of its telomere-lengthening function or telomerase activity. hTERT and EMT marker expression correlates positively in GC samples. Mouse experiments demonstrate the in vivo stimulation of hTERT on cancer cell colonization. Collectively, hTERT stimulates EMT and induces stemness of cancer cells, thereby promoting cancer metastasis and recurrence. Thus, targeting hTERT may prevent cancer progression by inhibiting EMT and CSCs.