LincRNA-p21 Impacts Prognosis in Resected Non-Small Cell Lung Cancer Patients through Angiogenesis Regulation
LincRNA-p21 Impacts Prognosis in Resected Non-Small Cell Lung Cancer Patients through Angiogenesis Regulation
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DOI：
10.1016/j.jtho.2016.07.015
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发表时间：
2016-12-01
影响因子：
20.4
通讯作者：
Monzo, Mariano
中科院分区：
文献类型：
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作者：
Castellano, Joan J.;Navarro, Alfons;Monzo, Mariano
前言：长基因间非编码RNA-p21(lincRNA-p21)是一种由肿瘤蛋白p53(TP53)和缺氧诱导因子1α亚基(HIF1a)转录激活的长非编码RNA。它参与了TP53依赖的细胞凋亡和Warburg效应的调节。我们探讨了lincRNA-p21在非小细胞肺癌中的作用。方法：检测128例非小细胞肺癌患者肿瘤组织和正常组织中lincRNA-p21的表达，并与肿瘤复发时间和肿瘤特异性生存期(Css)相关。在lincRNA-p21沉默后，H23、H1299和HCC-44细胞系在低氧条件下培养。利用TaqMan人血管生成芯片研究血管生成相关基因的表达。采用酶联免疫吸附试验检测细胞培养上清液中血管内皮生长因子A蛋白的水平。用人脐静脉内皮细胞管形成实验检测血管生成能力。结果：lincRNA-p21在肿瘤组织中表达下调，但与TP53基因突变状态无关。在所有患者中，高水平的lincRNA-p21与较差的css相关(p=0.032)。当根据组织学亚型对患者进行分类时，lincRNA-p21的影响仅限于腺癌复发时间(p=0.006)和慢性粒细胞癌患者(p<；0.001)。为了解释lincRNA-p21高表达患者预后不良的原因，我们研究了lincRNA-p21在体外血管生成中的作用，并观察到当lincRNAp21被抑制时，血管生成相关基因的表达全面下调。此外，lincRNAp21抑制的细胞培养上清液的血管生成和分泌的血管内皮生长因子A水平明显低于对照组。结论：我们的研究结果提示lincRNA-p21通过调节血管生成影响NSCLC腺癌患者的预后。(C)2016年国际肺癌研究协会。爱思唯尔公司出版，版权所有。
Introduction: Long intergenic noncoding RNA-p21 (lincRNA-p21) is a long noncoding RNA transcriptionally activated by tumor protein p53 (TP53) and hypoxia inducible factor 1 alpha subunit (HIF1A). It is involved in the regulation of TP53-dependent apoptosis and the Warburg effect. We have investigated the role of lincRNA-p21 in NSCLC.Methods: LincRNA-p21 expression was assessed in tumor and normal tissue from 128 patients with NSCLC and correlated with time to relapse and cancer-specific survival (CSS). H23, H1299, and HCC-44 cell lines were cultured in hypoxic conditions after silencing of lincRNA-p21. The TaqMan human angiogenesis array was used to explore angiogenesis-related gene expression. Levels of the protein vascular endothelial growth factor A were measured by enzyme-linked immunosorbent assay in the cell supernatants. Angiogenic capability was measured by human umbilical vein endothelial cell tube formation assay. Microvascular density in tumor samples was analyzed by immunohistochemistry.Results: LincRNA-p21 was down-regulated in tumor tissue, but no association was observed with TP53 mutational status. High lincRNA-p21 levels were associated with poor CSS in all patients (p = 0.032). When patients were classified according to histological subtypes, the impact of lincRNA-p21 was confined to patients with adenocarcinoma in both time to relapse (p = 0.006) and CSS (p < 0.001). To explain the poor outcome of patients with high lincRNA-p21 expression, we studied the role of lincRNA-p21 in angiogenesis in vitro and observed a global downregulation in the expression of angiogenesis-related genes when lincRNAp21 was inhibited. Moreover, supernatants from lincRNAp21-inhibited cells were significantly less angiogenic and had lower levels of secreted vascular endothelial growth factor A than controls did. Finally, tumor samples with high lincRNA-p21 levels had higher microvascular density.Conclusions: Our findings suggest that lincRNA-p21 affects outcome in patients with NSCLC adenocarcinoma through the regulation of angiogenesis. (C) 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.