Upregulated expression of Nucleostemin/GNL3 is associated with poor prognosis and Sorafenib Resistance in Hepatocellular Carcinoma
Upregulated expression of Nucleostemin/GNL3 is associated with poor prognosis and Sorafenib Resistance in Hepatocellular Carcinoma
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Nucleostemin/GNL3 表达上调与肝细胞癌预后不良和索拉非尼耐药相关
DOI：
10.1016/j.prp.2016.11.014
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发表时间：
2017-01-01
影响因子：
2.8
通讯作者：
Cui, Xiaopeng
中科院分区：
文献类型：
--
作者：
Hua, Lu;Hu, Baoying;Cui, Xiaopeng
核干细胞蛋白（NS）/GNL 3蛋白是一种在干细胞和癌细胞中大量表达的核仁蛋白。在此，我们发现NS在HCC组织中表达上调，并且NS的表达与p53的表达呈负相关。NS的过表达预示着HCC患者的预后显著恶化，提示NS可能作为HCC的预后标志物。此外，我们发现NS的耗竭使HCC细胞对索拉非尼诱导的凋亡敏感。此外，我们发现NS介导的索拉非尼耐药的机制涉及p53和下游Bax和Bcl-2蛋白的表达失调。在肝癌细胞中NS与p53相互作用。NS耗竭使p53和Bax表达增加，而使细胞Bcl-2水平降低。NS的干扰增强了索拉非尼对肝癌细胞的细胞毒作用。此外，异位表达NS损害索拉非尼暴露后的肝癌细胞凋亡。因此，NS可能通过调节p53通路和Bcl-2蛋白参与肝癌细胞对索拉非尼的耐药。这些发现表明，沉默NS表达和索拉非尼治疗的组合是治疗HCC的有希望的治疗策略。(C)2016年爱思唯尔有限公司。All rights reserved.
Nucleostemin (NS)/GNL3 protein has been recently documented to be a nucleolar protein that was abundantly expressed in stem cells and cancer cells. Herein, we showed that NS was upregulated in HCC tissues and the expression of NS was inversely correlated with that of p53. Overexpression of NS predicted significantly worsened prognosis in HCC patients, suggesting that NS might serve as a prognostic marker of HCC. In addition, we found that depletion of NS sensitized HCC cells to sorafenib-induced apoptosis. Moreover, we found that the mechanism underlying NS-mediated sorafenib resistance involved dysregulated expression of p53, and downstream Bax and Bcl-2 proteins. NS interacted with p53 in HCC cells. Depletion of NS increased the expression of p53 and Bax, whereas impaired the level of cellular Bcl-2. Interference of NS enhanced the cytotoxic effects of sorafenib in HCC cells. Furthermore, ectopic expression of NS impaired the apoptosis of HCC cells following sorafenib exposure. Therefore, NS may contribute to sorafenib resistance in HCC cells through the modulation of p53 pathway and Bcl-2 proteins. These findings indicated that the combination of silencing NS expression and sorafenib treatment is a promising therapeutic strategy in treatment of HCC. (C) 2016 Elsevier GmbH. All rights reserved.