LINC01572 通过调节 miRNA-338-5p/TTK 轴介导的 p53 促进肺腺癌的恶性进展。

LINC01572 promotes the malignant progression of lung adenocarcinoma by modulating p53 mediated by miRNA-338-5p/TTK axis.

机构信息

Department of Respiratory and Critical Care Medicine, Chengdu Fifth People's Hospital (The Second Clinical Medical College, Affiliated Fifth People's Hospital of Chengdu University of Traditional Chinese Medicine), Chengdu 611130, China.

出版信息

J Pharm Pharmacol. 2024 Jul 5;76(7):873-883. doi: 10.1093/jpp/rgad128.

DOI:10.1093/jpp/rgad128

PMID:38698658

Abstract

OBJECTIVES

Lung cancer is one of the malignant tumors that threaten human health seriously. Long non-coding RNA (lncRNA) is an important factor affecting tumorigenesis and development. However, the mechanism of lncRNA in lung cancer progression remains to be further explored.

METHODS

In this study, the TCGA database was analyzed, and LINC01572 was found to be increased in lung adenocarcinoma (LUAD) tissues. Thereafter, with the help of databases including lncBase, TargetScan, and mirDIP, as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, LINC01572/miRNA-338-5p/TTK regulatory axis and downstream p53 signaling pathway were excavated. qRT-PCR was adopted to detect levels of LINC01572, miRNA-338-5p, and TTK in LUAD cells. The role that LINC01572 played in LUAD cells was validated by CCK-8 assay, flow cytometry, colony formation, Transwell, and scratch healing assays. The binding ability between LINC01572/TTK and miRNA-338-5p was then verified by dual-luciferase and RIP analysis.

KEY FINDINGS

The results of this study demonstrated that LINC01572 was elevated in LUAD cells compared with normal cells. The overexpression of LINC01572 promoted the proliferative and migratory properties of LUAD cells but inhibited cell apoptosis. The inhibition of LINC01572 resulted in the opposite result. In addition, rescue experiments revealed that LINC01572, as a molecular sponge of miRNA-338-5p, targeted TTK to manipulate p53 for facilitating LUAD cell malignant progression. Apart from this, we constructed a mouse xenograft model and confirmed that the knockdown of LINC01572 hindered the growth of LUAD solid tumors in vivo.

CONCLUSIONS

Our findings illuminated the molecular mechanism of LINC01572 influencing LUAD and provided new insights for targeted therapy of LUAD cells.

摘要

目的

肺癌是严重威胁人类健康的恶性肿瘤之一。长链非编码 RNA（lncRNA）是影响肿瘤发生发展的重要因素。然而，lncRNA 在肺癌进展中的作用机制仍有待进一步探讨。

方法

本研究分析了 TCGA 数据库，发现 LINC01572 在肺腺癌（LUAD）组织中升高。此后，借助 lncBase、TargetScan 和 mirDIP 等数据库以及京都基因与基因组百科全书（KEGG）富集分析，挖掘出 LINC01572/miRNA-338-5p/TTK 调控轴及其下游 p53 信号通路。采用 qRT-PCR 检测 LUAD 细胞中 LINC01572、miRNA-338-5p 和 TTK 的水平。通过 CCK-8 检测、流式细胞术、集落形成、Transwell 和划痕愈合试验验证 LINC01572 在 LUAD 细胞中的作用。通过双荧光素酶和 RIP 分析验证 LINC01572/TTK 与 miRNA-338-5p 的结合能力。

主要发现

本研究结果表明，与正常细胞相比，LINC01572 在 LUAD 细胞中上调。LINC01572 的过表达促进了 LUAD 细胞的增殖和迁移特性，但抑制了细胞凋亡。LINC01572 的抑制则产生相反的结果。此外，挽救实验表明，LINC01572 作为 miRNA-338-5p 的分子海绵，靶向 TTK 以操纵 p53，从而促进 LUAD 细胞的恶性进展。除此之外，我们构建了小鼠异种移植模型，并证实了 LINC01572 的敲低在体内抑制了 LUAD 实体瘤的生长。