NRBP2 Overexpression Increases the Chemosensitivity of Hepatocellular Carcinoma Cells via Akt Signaling
NRBP2 Overexpression Increases the Chemosensitivity of Hepatocellular Carcinoma Cells via Akt Signaling
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NRBP2 过表达通过 Akt 信号传导增加肝细胞癌细胞的化疗敏感性
DOI：
10.1158/0008-5472.can-16-0937
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发表时间：
2016-12-01
期刊：
影响因子：
11.2
通讯作者：
Li, Jinjun
中科院分区：
文献类型：
--
作者：
Zhang, Lixing;Ge, Chao;Li, Jinjun
肝细胞癌对化疗具有高度耐药性。研究表明，肿瘤干细胞（CSC）可能是导致化疗耐药的重要因素，抑制CSC干细胞性的策略也可以抑制肿瘤耐药。在本研究中，我们发现核受体结合蛋白2（NRBP 2）在CD 133（+）肝细胞癌CSCs中表达下调。与肝癌患者癌组织相比，所分析的大多数癌旁肝组织中NRBP 2表达水平较高，且NRBP 2高表达表明预后较好。实时荧光定量PCR结果显示，NRBP 2与干细胞相关基因Oct 3/4、Nanog、Notch 1、Ep 300和CD 133 mRNA表达呈负相关。NRBP 2高表达可下调肝癌细胞CK 19蛋白的表达，抑制肿瘤球的形成，抑制肝癌细胞的成瘤能力，表明NRBP 2高表达抑制肝癌细胞的干细胞性。NRBP 2的过表达降低了索拉非尼在肝癌细胞中的IC 50，并且NRBP 2的表达与肝癌细胞对化疗药物（包括顺铂和Akt信号抑制剂哌立福辛）的耐药性呈负相关。免疫共沉淀结果显示NRBP 2可与膜联蛋白A2（ANXA 2）结合并抑制ANXA 2的表达。ANXA 2的共表达恢复了NRBP 2过表达肝癌细胞的化疗耐药能力。进一步分析表明NRBP 2下调Akt及其下游信号靶点Bad的磷酸化水平。ANXA 2共表达部分恢复Akt磷酸化。Bcl 2家族蛋白表达分析表明NRBP 2可能通过调节Akt和Bcl 2通路中生存蛋白的表达而增加肝癌细胞的化疗敏感性。这些结果表明，NRBP 2在肝癌的肿瘤进展和化疗耐药中起重要作用。(C)2016年AACR。
Hepatocellular carcinoma is highly resistant to chemotherapy. Research data supported that cancer stem cells (CSC) may be responsible for the chemoresistance and strategies that suppress CSCs stemness could also inhibit the drug resistance. In this study, we found that nuclear receptor binding protein 2 (NRBP2) expression was downregulated in the CD133(+) hepatocellular carcinoma CSCs. Most adjacent noncancerous liver tissue analyzed expressed higher level of NRBP2 compared with cancerous tissue in hepatocellular carcinoma patients, and high NRBP2 expression indicated a better prognosis. Real-time PCR results showed that NRBP2 negatively correlated with stemness-related genes, including Oct3/4, Nanog, Notch1, Ep300, and CD133 mRNA expression. High NRBP2 expression in hepatocellular carcinoma cells downregulated CK19 protein expression, inhibited tumor-sphere formation, and tumorigenesis ability, indicating that high NRBP2 expression restrains the hepatocellular carcinoma cell stemness. Overexpression of NRBP2 reduced the IC50 of sorafenib in hepatocellular carcinoma cells, and NRBP2 expression was negatively correlated with hepatocellular carcinoma cell resistance to the chemotherapy agents, including cisplatin and the Akt signaling inhibitor perifosine. Coimmunoprecipitation results showed that NRBP2 could bind with Annexin A2 (ANXA2) and inhibit ANXA2 expression. Coexpression of ANXA2 restored the chemoresistant ability in NRBP2-overexpressing hepatocellular carcinoma cells. Further analysis showed that NRBP2 downregulated Akt and its downstream signaling target Bad phosphorylation level. ANXA2 coexpression partially restored the Akt phosphorylation. Analysis of the expression of Bcl2 family proteins showed that NRBP2 may increase hepatocellular carcinoma cell chemosensitivity by regulating expression of survival proteins involved in the Akt and Bcl2 pathway. These results suggest that NRBP2 plays an important role in the tumor progression and chemotherapeutic resistance of hepatocellular carcinoma. (C) 2016 AACR.