The miR-204-3p-targeted IGFBP2 pathway is involved in xanthohumol-induced glioma cell apoptotic death
The miR-204-3p-targeted IGFBP2 pathway is involved in xanthohumol-induced glioma cell apoptotic death
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DOI：
10.1016/j.neuropharm.2016.07.038
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发表时间：
2016-11-01
影响因子：
4.7
通讯作者：
Chen, Ku-Chung
中科院分区：
文献类型：
--
作者：
Chen, Peng-Hsu;Chang, Cheng-Kuei;Chen, Ku-Chung
黄腐醇（XN）是一种从啤酒花植物葎草（大麻科）中提取的异戊烯基查尔酮，在包括神经胶质瘤在内的癌症治疗方面具有潜力。微小（mi）RNA是一类控制基因表达的小分子非编码RNA。已经发现有几种miRNA参与调节神经胶质瘤的发展。然而，尚无研究表明miRNA是否参与XN的细胞毒性作用从而导致神经胶质瘤细胞死亡。本研究探讨了XN介导的miRNA表达在激活胶质母细胞瘤U87 MG细胞凋亡通路中的作用。首先，我们发现XN通过促半胱天冬酶 - 3/8裂解和聚（ADP - 核糖）聚合酶（PARP）降解显著降低细胞活力并诱导细胞凋亡。我们还确定促半胱天冬酶 - 9裂解、Bcl（2）家族表达变化、线粒体功能障碍以及细胞内活性氧（ROS）的产生也参与了XN诱导的神经胶质瘤细胞死亡。通过微阵列分析，miR - 204 - 3p被确定为XN细胞毒性诱导下上调最显著的miRNA。细胞外信号调节激酶（ERK）/c - Fos通路被证实参与XN上调的miR - 204 - 3p表达。通过启动子分析和染色质免疫沉淀（ChIP）分析，我们发现c - Fos与miR - 204 - 3p基因启动子区域呈剂量依赖性结合。此外，与星形胶质细胞相比，几种神经胶质瘤细胞系中的miR - 204 - 3p水平降低。miR - 204 - 3p的过表达增强了神经胶质瘤细胞的凋亡。胰岛素样生长因子结合蛋白2（IGFBP2）是一种神经胶质瘤增殖的上调调节因子，通过癌症基因组图谱（TCGA）分析被证实为miR - 204 - 3p的直接靶基因。XN通过miR - 204 - 3p靶向抑制IGFBP2/AKT/Bcl2通路在介导神经胶质瘤细胞死亡中起关键作用。这些结果强调XN介导的miR - 204 - 3p网络可能为未来胶质母细胞瘤的治疗和药物开发提供新的治疗策略。（C）2016爱思唯尔有限公司。保留所有权利。
Xanthohumol (XN), a prenylated chalcone extracted from hop plant Humulus lupulus L. (Cannabaceae), has potential for cancer therapy, including gliomas. Micro (mi)RNAs are small noncoding RNAs that control gene expression. Several miRNAs have been identified to participate in regulating glioma development. However, no studies have demonstrated whether miRNA is involved in XN cytotoxicity resulting in glioma cell death. This study investigated the effects of XN-mediated miRNA expression in activating apoptotic pathways in glioblastoma U87 MG cells. First, we found that XN significantly reduced cell viability and induced apoptosis via pro-caspase-3/8 cleavage and poly(ADP ribose) polymerase (PARP) degradation. We also identified that pro-caspase-9 cleavage, Bcl(2) family expression changes, mitochondrial dysfunction, and intracellular ROS generation also participated in XN-induced glioma cell death. With a microarray analysis, miR-204-3p was identified as the most upregulated miRNA induced by XN cytotoxicity. The extracellular signal-regulated kinase (ERK)/c-Fos pathway was validated to participate in XN-upregulated miR-204-3p expression. With a promoter assay and ChIP analysis, we found that c-Fos dose-dependently bound to the miR-204-3p gene promoter region. Furthermore, miR-204-3p levels decreased in several glioma cell lines compared to astrocytes. Over expression of miR-204-3p enhanced glioma cell apoptosis. IGFBP2, an upregulated regulator of glioma proliferation, was validated by a TCGA analysis as a direct target gene of miR-204-3p. XN's inhibition of the IGFBP2/AKT/Bcl2 pathway via miR-204-3p targeting played a critical role in mediating glioma cell death. These results emphasized that the XN-mediated miR-204-3p network may provide novel therapeutic strategies for future glioblastoma therapy and drug development. (C) 2016 Elsevier Ltd. All rights reserved.