Department of Thoracic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Eur Rev Med Pharmacol Sci. 2020 May;24(9):4822-4835. doi: 10.26355/eurrev_202005_21171.
Previous studies have proved that lncRNA MIR155 host gene (MIR155HG) is overexpressed in glioma and has elucidated its function. However, its functional role and underlying molecular mechanism in non-small cell lung cancer (NSCLC) are unknown. This study aimed to investigate the function and underlying mechanism of MIR155HG in NSCLC.
Differentially expressed lncRNAs in NSCLC tissue were identified from Gene Expression Omnibus (GEO) database. The expression of MIR155HG, miR-155-3p, miRNA-155-5p, and tumor protein p53-inducible nuclear protein 1 (TP53INP1) in NSCLC specimens and cells were quantified using quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and Western blotting analysis. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and transwell invasion assay were performed to evaluate cell viability and the ability of migration and invasion. Luciferase reporter assay was employed to examine whether miR-155-3p and miR-155-5p could bind to TP53INP1 in NSCLC cells. A xenograft tumor model was used to evaluate the biological function of MIR155HG in vivo.
Data obtained from the GEO dataset show that MIR155HG is frequently overexpressed in NSCLC tumor tissues and cell lines. Elevated MIR155HG levels were found to be associated with advanced disease stage and poor prognosis of NSCLC. Cell viability, as well as the capability of migration and invasion of NCI-H1975 and A549 cells, was markedly reduced upon MIR155HG knockdown. Mechanistically, bioinformatics analysis and functional assays confirmed that miR-155-5p and miR-155-3p, two derivatives of MIR155HG, contributed to the effect of MIR155HG in NSCLC. It was also found that miR-155-5p or miR-155-3p mimics could dramatically rescue the inhibition of cell proliferation, migration, and invasion caused by siMIR155HG. Furthermore, bioinformatics analysis and Luciferase reporter assays revealed that miR-155-5p and miR-155-3p mediate the effect of MIR155HG in NSCLC cells by negatively regulating the tumor suppressor TP53INP1.
Current findings indicate that MIR155HG/miR-155 axis facilitates NSCLC progression by downregulating TP53INP1. Therefore, the MIR155HG/miR-155 axis may be a potential therapeutic target for NSCLC.
先前的研究已经证明，长链非编码 RNA MIR155 宿主基因（MIR155HG）在神经胶质瘤中过度表达，并阐明了其功能。然而，其在非小细胞肺癌（NSCLC）中的功能作用及其潜在的分子机制尚不清楚。本研究旨在探讨 MIR155HG 在 NSCLC 中的功能和潜在机制。
从基因表达综合数据库（GEO）中鉴定 NSCLC 组织中差异表达的 lncRNA。使用实时定量聚合酶链反应（qRT-PCR）和 Western blot 分析定量检测 NSCLC 标本和细胞中 MIR155HG、miR-155-3p、miR-155-5p 和肿瘤蛋白 p53 诱导核蛋白 1（TP53INP1）的表达。采用 3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴盐（MTT）检测法和 Transwell 侵袭试验评估细胞活力以及迁移和侵袭能力。利用荧光素酶报告基因检测分析 miR-155-3p 和 miR-155-5p 是否能与 NSCLC 细胞中的 TP53INP1 结合。采用异种移植肿瘤模型评估 MIR155HG 在体内的生物学功能。
来自 GEO 数据集的数据表明，MIR155HG 在 NSCLC 肿瘤组织和细胞系中频繁过表达。研究发现，升高的 MIR155HG 水平与 NSCLC 的晚期疾病阶段和不良预后相关。NCI-H1975 和 A549 细胞中 MIR155HG 的敲低显著降低了细胞活力以及迁移和侵袭能力。通过生物信息学分析和功能测定证实，MIR155HG 的两个衍生物 miR-155-5p 和 miR-155-3p 有助于 MIR155HG 在 NSCLC 中的作用。还发现 miR-155-5p 或 miR-155-3p 模拟物可显著挽救 siMIR155HG 引起的细胞增殖、迁移和侵袭抑制作用。此外，生物信息学分析和荧光素酶报告基因检测表明，miR-155-5p 和 miR-155-3p 通过负调控肿瘤抑制因子 TP53INP1 介导 MIR155HG 在 NSCLC 细胞中的作用。
目前的研究结果表明，MIR155HG/miR-155 轴通过下调 TP53INP1 促进 NSCLC 进展。因此，MIR155HG/miR-155 轴可能成为 NSCLC 的潜在治疗靶点。
