Twisted epithelial-to-mesenchymal transition promotes progression of surviving bladder cancer T24 cells with hTERT-dysfunction.
Twisted epithelial-to-mesenchymal transition promotes progression of surviving bladder cancer T24 cells with hTERT-dysfunction.
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DOI：
10.1371/journal.pone.0027748
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
He D
中科院分区：
文献类型：
--
作者：
Xue Y;Li L;Zhang D;Wu K;Chen Y;Zeng J;Wang X;He D
人类癌细胞维持端粒，通过端粒酶活性(TA)或不同类型细胞中端粒的替代延长(ALT)来保护细胞免受衰老。此外，在不同的实体肿瘤中，在肿瘤进展过程中，上皮向间充质转化(EMT)可以绕过细胞衰老。然而，端粒酶逆转录酶功能异常的膀胱癌T24细胞经长期培养后端粒维持和进展能力的特征尚未阐明。本研究利用显性负性突变型人端粒酶逆转录酶(HTERT)载体抑制膀胱癌T24细胞TA，观察到27代后T24/DN868A细胞出现长端粒长表型和ALT相关的PML小体(APB)复合体，提示在端粒酶抑制的T24/DN868A细胞中存在类ALT途径。同时，端粒酶抑制导致了显著的EMT，表现为细胞形态的改变伴随着EMT标志物的变化。存活的T24/DN868A细胞在体外和体内均表现出更强的进展能力。此外，我们还发现在存活的T24/DN868A样本中，Twist被激活以介导EMT。综上所述，我们的研究结果表明，膀胱癌T24细胞可能通过促进EMT而发生端粒酶向ALT样转化并促进晚期肿瘤进展，从而为肿瘤治疗中端粒酶抑制剂耐药的机制提供了新的可能的见解。
Human cancer cells maintain telomeres to protect cells from senescence through telomerase activity (TA) or alternative lengthening of telomeres (ALT) in different cell types. Moreover, cellular senescence can be bypassed by Epithelial-to-mesenchymal transition (EMT) during cancer progression in diverse solid tumors. However, it has not been elucidated the characteristics of telomere maintenance and progression ability after long-term culture in bladder cancer T24 cells with hTERT dysfunction. In this study, by using a dominant negative mutant human telomerase reverse transcriptase (hTERT) vector to inhibit TA in bladder cancer T24 cells, we observed the appearance of long phenotype of telomere length and the ALT-associated PML body (APB) complex after the 27th passage, indicating the occurrence of ALT-like pathway in surviving T24/DN868A cells with telomerase inhibition. Meanwhile, telomerase inhibition resulted in significant EMT as shown by change in cellular morphology concomitant with variation of EMT markers. Consistently, the surviving T24/DN868A cells showed increased progression ability in vitro and in vivo. In addition, we found Twist was activated to mediate EMT in surviving T24/DN868A samples. Taken together, our findings indicate that bladder cancer T24 cells may undergo the telomerase-to-ALT-like conversion and promote cancer progression at advanced stages through promoting EMT, thus providing novel possible insight into the mechanism of resistance to telomerase inhibitors in cancer treatment.
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