Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain.
Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain.
J Thorac Oncol. 2016 Dec;11(12):2173-2182. doi: 10.1016/j.jtho.2016.07.015. Epub 2016 Aug 2.
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 lincRNA-p21 was inhibited. Moreover, supernatants from lincRNA-p21-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.
简介：长链非编码 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) 转录激活的长链非编码 RNA。它参与了 TP53 依赖性凋亡和瓦博格效应的调节。我们研究了 lincRNA-p21 在 NSCLC 中的作用。
方法：评估了 128 例 NSCLC 患者肿瘤组织和正常组织中的 lincRNA-p21 表达情况，并与复发时间和癌症特异性生存(CSS)相关联。在沉默 lincRNA-p21 后，将 H23、H1299 和 HCC-44 细胞系在低氧条件下培养。使用 TaqMan 人类血管生成阵列探索血管生成相关基因表达。通过酶联免疫吸附试验测量细胞上清液中血管内皮生长因子 A 的蛋白水平。通过人脐静脉内皮细胞管形成试验测量血管生成能力。通过免疫组织化学分析肿瘤样本中的微血管密度。
结果：lincRNA-p21 在肿瘤组织中下调，但与 TP53 突变状态无关。所有患者中，高 lincRNA-p21 水平与 CSS 不良相关(p=0.032)。当根据组织学亚型对患者进行分类时，lincRNA-p21 的影响仅限于腺癌患者，无论是在复发时间(p=0.006)还是 CSS(p<0.001)。为了解释高 lincRNA-p21 表达患者的不良预后，我们研究了 lincRNA-p21 在体外血管生成中的作用，观察到当抑制 lincRNA-p21 时，血管生成相关基因的表达出现全面下调。此外，与对照组相比，抑制 lincRNA-p21 的细胞上清液的血管生成能力显著降低，分泌的血管内皮生长因子 A 水平也较低。最后，高 lincRNA-p21 水平的肿瘤样本具有更高的微血管密度。
结论：我们的研究结果表明，lincRNA-p21 通过调节血管生成影响 NSCLC 腺癌患者的预后。
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