The NRF2-dependent transcriptional axis, XRCC5/hTERT drives tumor progression and 5-Fu insensitivity in hepatocellular carcinoma.
The NRF2-dependent transcriptional axis, XRCC5/hTERT drives tumor progression and 5-Fu insensitivity in hepatocellular carcinoma.
复制标题
NRF 2依赖性转录轴XRCC 5/hTERT驱动肝细胞癌的肿瘤进展和5-Fu不敏感性。
DOI：
10.1016/j.omto.2021.12.012
复制
发表时间：
2022-03-17
期刊：
影响因子：
--
通讯作者：
Deng W
中科院分区：
文献类型：
--
作者：
Liu T;Long Q;Li L;Gan H;Hu X;Long H;Yang L;Pang P;Wang S;Deng W
人端粒酶逆转录酶（human telomerase reverse transcriptase，hTERT）在多种肿瘤中高度表达，在多种肿瘤的发生和转移过程中起重要作用。然而，其在肝细胞癌（HCC）中高表达的分子机制尚不清楚。在这项研究中，我们确定了X射线修复交叉互补5（XRCC5），一个新的hTERT启动子结合蛋白在肝癌细胞，使用生物素-链霉亲和素-琼脂糖下拉分析。我们发现XRCC5在HCC细胞中高度表达，在HCC细胞中它上调hTERT的转录。在功能上，XRCC5的转基因表达促进HCC进展和5-氟尿嘧啶抗性，而XRCC5的短发夹RNA敲除在体外和体内具有相反的作用。此外，hTERT过表达逆转了XRCC5敲低或5-氟尿嘧啶（5-Fu）介导的HCC抑制。机制上，核因子红细胞-2相关因子2（NRF2）与XRCC 5相互作用，进而上调hTERT。然而，当NRF2减少时，上调不显著，表明XRCC 5介导的hTERT表达是NRF2依赖性的。与肿瘤组织中XRCC5和hTERT水平低的患者相比，XRCC5和hTERT高表达水平的HCC患者的总生存时间较短。总的来说，我们的研究证明了XRCC5/NRF2/hTERT信号传导在HCC转移中的分子机制，这将有助于确定HCC诊断和治疗的新策略。我们已经探索了肿瘤特异性表达和激活hTERT的分子机制。此外，我们首次证明了XRCC5以NRF2依赖性方式转录激活hTERT，从而阐明了HCC中hTERT激活和上调的分子机制。
Human telomerase reverse transcriptase (hTERT) is highly expressed in many tumors and is essential for tumorigenesis and metastasis in multiple cancers. However, the molecular mechanisms underlying its high expression level in hepatocellular carcinoma (HCC) remain unclear. In this study, we identified X-ray repair cross-complementing 5 (XRCC5), a novel hTERT promoter-binding protein in HCC cells, using biotin-streptavidin-agarose pull-down assay. We found that XRCC5 was highly expressed in HCC cells, in which it transcriptionally upregulated hTERT. Functionally, the transgenic expression of XRCC5 promoted HCC progression and 5-fluorouracil resistance, whereas short hairpin RNA knockdown of XRCC5 had converse effects in vitro and in vivo. Moreover, hTERT overexpression reversed XRCC5 knockdown- or 5-fluorouracil (5-Fu)-mediated HCC inhibition. Mechanistically, nuclear-factor-erythroid-2-related factor 2 (NRF2) interacted with XRCC5, which in turn upregulated hTERT. However, the upregulation was insignificant when NRF2 was reduced, suggesting that the XRCC5-mediated hTERT expression was NRF2 dependent. The HCC patients with high expression levels of XRCC5 and hTERT had shorter overall survival times compared with those with low XRCC5 and hTERT levels in their tumor tissues. Collectively, our study demonstrates the molecular mechanisms of the XRCC5/NRF2/hTERT signaling in HCC metastasis, which will aid in the identification of novel strategies for the diagnosis and treatment of HCC. We have explored the molecular mechanisms underlying the tumor-specific expression and activation of hTERT. Moreover, we have demonstrated for the first time that hTERT is transcriptionally activated by XRCC5 in a NRF2-dependent manner, thereby throwing light on the molecular mechanisms underlying the activation and upregulation of hTERT in HCC.
登录
查看更多内容
将聚（ADP-核糖）聚合酶-1和KU70/KU80鉴定为S100A9基因表达的转录调节剂。
影响因子：
--
作者：
Grote, Jens;Koenig, Simone;Ackermann, Doreen;Sopalla, Claudia;Benedyk, Malgorzata;Los, Marek;Kerkhoff, Claus
通讯作者：
Kerkhoff, Claus
端粒DNA合成过程中端粒酶RNA定位的RNA手风琴模型。
影响因子：
16.8
作者：
Berman, Andrea J.;Akiyama, Benjamin M.;Stone, Michael D.;Cech, Thomas R.
通讯作者：
Cech, Thomas R.
Tbx3 的新型 HDAC5 相互作用基序对于抑制 E-钙粘蛋白表达和促进肝细胞癌转移至关重要
影响因子：
39.3
作者：
Dong L;Dong Q;Chen Y;Li Y;Zhang B;Zhou F;Lyu X;Chen GG;Lai P;Kung HF;He ML
通讯作者：
He ML
DOI：
10.1073/pnas.172398899
发表时间：
2002-09-03
影响因子：
11.1
作者：
Dinkova-Kostova, AT;Holtzclaw, WD;Talalay, P
通讯作者：
Talalay, P
影响因子：
25.7
作者：
El-Serag, HB;Siegel, AB;McGlynn, KA
通讯作者：
McGlynn, KA