Upregulated miR-182 increases drug resistance in cisplatin-treated HCC cell by regulating TP53INP1
Upregulated miR-182 increases drug resistance in cisplatin-treated HCC cell by regulating TP53INP1
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DOI：
10.1016/j.gene.2013.12.043
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发表时间：
2014-04-01
期刊：
影响因子：
3.5
通讯作者：
Chen, Wei
中科院分区：
文献类型：
--
作者：
Qin, Jun;Luo, Meng;Chen, Wei
化疗在肝细胞癌（HCC）治疗中起着至关重要的作用，尤其是对于晚期HCC患者。顺铂是治疗肝癌的常用化疗药物之一。然而，获得顺铂耐药是常见的HCC患者，这种耐药的潜在机制尚未完全了解。在这项研究中，我们专注于确定miRNA在顺铂为基础的联合化疗后化疗耐药性中的作用。我们检测了晚期肝癌患者接受顺铂化疗后miR-182的表达水平，并通过实时荧光定量PCR分析和CCK-8检测明确了其生物学功能。我们发现，miR-182水平在接受顺铂化疗的HCC患者中显著升高。miR-182在顺铂耐药HepG 2（HepG 2-R）细胞中的水平也高于HepG 2细胞。在顺铂处理期间，上调的miR-182显著增加了细胞活力，而miR-182敲低降低了细胞活力。miR-182抑制也部分克服了HepG 2-R细胞中的顺铂耐药性。此外，我们发现上调的miR-182在体外抑制肿瘤抑制基因TP 53 INP 1（tumor protein 53-induced nuclear protein 1）的表达。在体内，miR-182与TP 53 INP 1表达呈负相关。我们最终证明miR-182增加了HCC细胞的顺铂耐药性，部分是通过靶向TP 53 INP 1。这些数据表明，miR-182/TP 53 INP 1信号通路代表了一个新的途径调节化疗耐药性，从而为HCC的化疗提供了一个新的靶点。(C)2013爱思唯尔有限公司版权所有。
Chemotherapy plays a crucial role in hepatocellular carcinoma (HCC) treatment especially for patients with advanced HCC. Cisplatin is one of the commonly used chemotherapeutic drugs for the treatment of HCC. However, acquisition of cisplatin resistance is common in patients with HCC, and the underlying mechanism of such resistance is not fully understood. In the study, we focused on identifying the role of miRNAs in chemotherapy resistance after cisplatin-based combination chemotherapy. We assayed the expression level of miR-182 after cisplatin-based chemotherapy in patients with advanced HCC, and defined the biological functions by real-time PCR analysis and CCK-8 assay. We found that miR-182 levels were significantly increased in HCC patients treated with cisplatin-based chemotherapy. miR-182 levels were also higher in cisplatin-resistant HepG2 (HepG2-R) cells than in HepG2 cells. Upregulated miR-182 significantly increased the cell viability, whereas miR-182 knockdown reduced the cell viability during cisplatin treatment. miR-182 inhibition also partially overcame cisplatin resistance in HepG2-R cell. Furthermore, we found that upregulated miR-182 inhibited the expression of tumor suppressor gene TP53INP1 (tumor protein 53-induced nuclear protein1) in vitro. In vivo, miR-182 and TP53INP1 expression was negatively correlated. We finally demonstrated that miR-182 increased cisplatin resistance of HCC cell, partly by targeting TP53INP1. These data suggest that miR-182/TP53INP1 signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of HCC. (C) 2013 Elsevier B.V. All rights reserved.