Targeting the NCOA3-SP1-TERT axis for tumor growth in hepatocellular carcinoma.
Targeting the NCOA3-SP1-TERT axis for tumor growth in hepatocellular carcinoma.
复制标题
靶向 NCOA3-SP1-TERT 轴促进肝细胞癌中的肿瘤生长。
DOI：
10.1038/s41419-020-03218-x
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发表时间：
2020-11-25
影响因子：
9
通讯作者：
Li L
中科院分区：
文献类型：
--
作者：
Li W;Yan Y;Zheng Z;Zhu Q;Long Q;Sui S;Luo M;Chen M;Li Y;Hua Y;Deng W;Lai R;Li L
肝细胞癌（HCC）死亡率高，缺乏有效的治疗靶点。人类端粒酶逆转录酶（TERT）的表达升高是癌症的一个重要标志，但TERT在癌症中被不同地激活的机制尚不清楚。在这里，我们已经确定了核受体共激活因子-3 （NCOA3）作为肝癌中TERT表达和肿瘤生长的新调节剂。NACO3特异性结合TERT启动子-234 ~ -144区域，通过转录激活TERT表达。在体外和体内，NCOA3通过上调TERT信号通路促进HCC细胞生长和肿瘤进展。NACO3敲低可抑制HCC细胞活力和集落形成，而TERT过表达可恢复这种抑制。NCOA3与TERT启动子相互作用并招募SP1结合。NCOA3的敲低也会抑制Wnt信号相关基因的表达，但对Notch信号靶向基因没有影响。此外，在HCC肿瘤组织中，NCOA3与TERT的表达呈正相关，NCOA3和TERT的高表达预示着HCC患者预后较差。我们的研究结果表明，靶向NCOA3-SP1-TERT信号轴可能对HCC患者有益。
Hepatocellular carcinoma (HCC) has a high mortality rate and lacks an effective therapeutic target. Elevated expression of human telomerase reverse transcriptase (TERT) is an important hallmark in cancers, but the mechanism by which TERT is activated differentially in cancers is poorly understood. Here, we have identified nuclear receptor coactivator-3 (NCOA3) as a new modulator of TERT expression and tumor growth in HCC. NACO3 specifically binds to the TERT promoter at the -234 to -144 region and transcriptionally activates TERT expression. NCOA3 promotes HCC cell growth and tumor progression in vitro and in vivo through upregulating the TERT signaling. Knockdown of NACO3 suppresses HCC cell viability and colony formation, whereas TERT overexpression rescues this suppression. NCOA3 interacts with and recruits SP1 binding on the TERT promoter. Knockdown of NCOA3 also inhibits the expression of the Wnt signaling-related genes but has no effect on the Notch signaling-targeting genes. Moreover, NCOA3 is positively correlated with TERT expression in HCC tumor tissues, and high expression of both NCOA3 and TERT predicts a poor prognosis in HCC patients. Our findings indicate that targeting the NCOA3-SP1-TERT signaling axis may benefit HCC patients.
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影响因子：
168.9
作者：
Lozano, Rafael;Naghavi, Mohsen;Murray, Christopher J. L.
通讯作者：
Murray, Christopher J. L.
影响因子：
5.1
作者：
Kulik, Laura M.;Chokechanachaisakul, Attasit
通讯作者：
Chokechanachaisakul, Attasit
DOI：
10.1016/j.bpg.2014.08.007
发表时间：
2014-10-01
影响因子：
3.2
作者：
Bosetti, Cristina;Turati, Federica;La Vecchia, Carlo
通讯作者：
La Vecchia, Carlo
影响因子：
--
作者：
Mussi, Paola;Yu, Chundong;Xu, Jianming
通讯作者：
Xu, Jianming
影响因子：
3.6
作者：
Bermudez Y;Erasso D;Johnson NC;Alfonso MY;Lowell NE;Kruk PA
通讯作者：
Kruk PA