NUPR1, a new target in liver cancer: implication in controlling cell growth, migration, invasion and sorafenib resistance.
NUPR1, a new target in liver cancer: implication in controlling cell growth, migration, invasion and sorafenib resistance.
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DOI：
10.1038/cddis.2016.175
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发表时间：
2016-06-23
影响因子：
9
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中科院分区：
文献类型：
--
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索拉非尼是一种口服多激酶抑制剂，是唯一被批准用于治疗晚期肝细胞癌（HCC）的药物。然而，它的益处是有限的，并且由于其作用机制仍然难以捉摸，因此需要更好地了解其抗癌作用。基于我们以前的研究结果，我们在这里研究核蛋白1（NUPR 1）在肝癌中的意义及其在索拉非尼治疗中的作用。NUPR 1是一种应激诱导蛋白，在多种恶性肿瘤中过表达，但其在HCC中的作用尚未完全了解。我们发现NUPR 1在原发性人HCC样本中的表达显著高于正常肝脏。NUPR 1的敲低显著增加了细胞对索拉非尼的敏感性，并在体外和体内抑制了HCC细胞的生长、迁移和侵袭。NUPR 1沉默影响RELB和IER 3基因的表达。不出所料，RELB和IER 3敲低也抑制HCC细胞活力、生长和迁移。使用稳定的NUPR 1敲低后HCC细胞的基因表达谱，我们发现功能上涉及细胞死亡和存活、细胞对治疗的反应、脂质代谢、细胞生长和增殖、分子转运和细胞运动的基因大多受到抑制。动态基因表达的网络分析确定NF-κB和ERK为下调的基因节点，并且一些HCC相关癌基因也被抑制。我们鉴定了Runt相关转录因子2（RUNX 2）基因作为NUPR 1调控的基因，并证明RUNX 2基因沉默抑制HCC细胞活力、生长、迁移和增加细胞对索拉非尼的敏感性。我们认为NUPR 1/RELB/IER 3/RUNX 2通路在肝癌发生中具有关键作用。NUPR 1/RELB/IER 3/RUNX 2通路作为一个潜在的治疗靶点的鉴定可能有助于肝癌管理新的治疗策略的发展。
Sorafenib, an oral multikinase inhibitor, is the only approved agent for the treatment of advanced hepatocellular carcinoma (HCC). However, its benefits are modest, and as its mechanisms of action remain elusive, a better understanding of its anticancer effects is needed. Based on our previous study results, we investigated here the implication of the nuclear protein 1 (NUPR1) in HCC and its role in sorafenib treatment. NUPR1 is a stress-inducible protein that is overexpressed in various malignancies, but its role in HCC is not yet fully understood. We found that NUPR1 expression was significantly higher in primary human HCC samples than in the normal liver. Knockdown of NUPR1 significantly increased cell sensitivity to sorafenib and inhibited the cell growth, migration and invasion of HCC cells, both in vitro and in vivo. Moreover, NUPR1 silencing influenced the expression of RELB and IER3 genes. Unsurprisingly, RELB and IER3 knockdown also inhibited HCC cell viability, growth and migration. Using gene expression profiling of HCC cells following stable NUPR1 knockdown, we found that genes functionally involved in cell death and survival, cellular response to therapies, lipid metabolism, cell growth and proliferation, molecular transport and cellular movement were mostly suppressed. Network analysis of dynamic gene expression identified NF-κB and ERK as downregulated gene nodes, and several HCC-related oncogenes were also suppressed. We identified Runt-related transcription factor 2 (RUNX2) gene as a NUPR1-regulated gene and demonstrated that RUNX2 gene silencing inhibits HCC cell viability, growth, migration and increased cell sensitivity to sorafenib. We propose that the NUPR1/RELB/IER3/RUNX2 pathway has a pivotal role in hepatocarcinogenesis. The identification of the NUPR1/RELB/IER3/RUNX2 pathway as a potential therapeutic target may contribute to the development of new treatment strategies for HCC management.
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影响因子：
4.3
作者：
Ding, Zhen;Qian, Ye-Ben;Xiong, Qi-Ru
通讯作者：
Xiong, Qi-Ru
影响因子：
8
作者：
Liao, Y-L;Sun, Y-M;Tsou, A-P
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Tsou, A-P
影响因子：
50.3
作者：
Carracedo, A;Lorente, M;Velasco, G
通讯作者：
Velasco, G
影响因子：
3.3
作者：
Chen, X;Cheung, ST;Brown, PO
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Brown, PO
鉴定用于建立多基因检测的基因，用于丙型肝炎病毒阳性肝硬化患者的肝细胞癌监测。
影响因子：
3.8
作者：
Archer, Kellie J.;Mas, Valeria R.;David, Krystle;Maluf, Daniel G.;Bornstein, Karen;Fisher, Robert A.
通讯作者：
Fisher, Robert A.