Noncoding telomeric repeat-containing RNA inhibits the progression of hepatocellular carcinoma by regulating telomerase-mediated telomere length
Noncoding telomeric repeat-containing RNA inhibits the progression of hepatocellular carcinoma by regulating telomerase-mediated telomere length
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含有非编码端粒重复序列的RNA通过调节端粒酶介导的端粒长度抑制肝细胞癌的进展
DOI：
10.1111/cas.14442
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发表时间：
2020-07-01
期刊：
影响因子：
5.7
通讯作者：
Ren, Tingting
中科院分区：
文献类型：
--
作者：
Cao, Haiyan;Zhai, Yulong;Ren, Tingting
端粒重复序列RNA（TERRA）与端粒长度的调控密切相关，端粒长度的调控在肿瘤发生中起着重要作用。然而，TERRA在肝细胞癌（HCC）中的生物学意义仍然很大程度上未知。在这项研究中，我们发现肝癌细胞显示TERRA及其正调节因子TTAGGG重复序列结合因子1（TRF 1）频繁下调，而负调节因子TTAGGG重复序列结合因子1（TRF 2）上调。我们发现TERRA、TRF 1和TRF 2与HCC患者的不良预后有关。重要的是，我们发现TERRA的下调在体外和体内显著促进HCC细胞的生长和转移，而TERRA的上调表现出相反的效果。从机制上讲，TERRA的下调显著增加了端粒酶活性，促进了端粒的延伸。此外，TERRA过表达对HCC细胞生长和转移的抑制作用可被激活端粒酶活性的TA-65逆转。相反，TERRA下调的促肿瘤作用被抑制端粒酶活性的TMPyP 4逆转。我们的研究结果表明，TERRA在肝癌细胞的生长和转移中起着至关重要的作用，表明TERRA是一个潜在的肝癌治疗靶点。
Telomeric repeat-containing RNA (TERRA) is closely involved in the regulation of telomere length, which plays critical roles in tumorigenesis. However, the biological significance of TERRA in hepatocellular carcinoma (HCC) remains largely unknown. In this study, we found that HCC cells show a frequent downregulation of TERRA and its positive regulator TTAGGG repeat binding factor-1 (TRF1), whereas the negative regulator TTAGGG repeat binding factor-1 (TRF2) was upregulated. We found that TERRA, TRF1, and TRF2 contributed to poor prognosis of HCC patients. Importantly, we found that the downregulation of TERRA significantly promoted HCC cell growth and metastasis in vitro and in vivo, whereas the upregulation of TERRA showed an opposite effect. Mechanistically, downregulation of TERRA significantly increased telomerase activity and promoted telomere elongation. Moreover, the inhibitory effects of TERRA overexpression on the growth and metastasis of HCC cells were reversed by treatment with TA-65 that activates telomerase activity. In contrast, the protumor effect of TERRA downregulation was reversed by treatment with TMPyP4 that inhibits telomerase activity. Our findings reveal that TERRA plays a critical role in HCC cell growth and metastasis, indicating that TERRA is a potential therapeutic target for HCC.