长链非编码RNA MIR4435-2HG通过靶向miR-371a-5p/SOX2/PI3K/Akt轴增强非小细胞肺癌细胞的迁移、增殖和糖酵解。

The long noncoding RNA MIR4435-2HG enhances the migration, promotion, and glycolysis of nonsmall cell lung cancer cells by targeting the miR-371a-5p/SOX2/PI3K/Akt axis.

作者信息

Yang Jin, Su Yu, Wang Yuchen, Gao Kun, Li Chuang, Li Mengmeng

机构信息

Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.

Department of Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.

出版信息

SAGE Open Med. 2024 Nov 8;12:20503121241289290. doi: 10.1177/20503121241289290. eCollection 2024.

DOI:10.1177/20503121241289290

PMID:39526092

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11549703/

Abstract

BACKGROUND

Nonsmall cell lung cancer is a leading cause of cancer-related death worldwide. The long noncoding RNA MIR4435-2HG has been shown to play a carcinogenic role in various cancers. The purpose of this study was to explore the role and regulatory mechanism of MIR4435-2HG in non-small cell lung cancer.

METHODS

Quantitative real-time polymerase chain reaction was used to detect MIR4435-2HG and SRY-box transcription factor 2 in nonsmall cell lung cancer cells. Gain- or loss-of-function assays of MIR4435-2HG and SRY-box transcription factor 2 were subsequently conducted. Cell proliferation, apoptosis, migration, glycolysis, and invasion were tested. A nude mouse tumor model was constructed to determine the role of MIR4435-2HG and SRY-box transcription factor 2 in the growth of tumor cells in vivo. Furthermore, the interactions between MIR4435-2HG, miR-371a-5p and SRY-box transcription factor 2 were analyzed via a dual-luciferase reporter gene assay.

RESULTS

Quantitative real-time polymerase chain reaction revealed that MIR4435-2HG and SRY-box transcription factor 2 were upregulated in nonsmall cell lung cancer cells. Forced MIR4435-2HG overexpression led to increased cell proliferation, migration, invasion, and glycolysis and repressed cell apoptosis. Overexpressing MIR4435-2HG promoted SRY-box transcription factor 2 expression and PI3K/Akt/mTOR pathway activation. Downregulating MIR4435-2HG had antitumor effects both in vitro and in vivo. SRY-box transcription factor 2 overexpression mostly reversed the suppressive effects of MIR4435-2HG downregulation. Mechanistic studies revealed that MIR4435-2HG, a competitive endogenous RNA, directly targeted and inhibited miR-371a-5p. Rescue assays revealed that miR-371a-5p overexpression or SRY-box transcription factor 2 downregulation significantly inhibited MIR4435-2HG-mediated oncogenic effects.

CONCLUSION

MIR4435-2HG promotes nonsmall cell lung cancer cell malignant behaviors and glycolysis by regulating the miR-371a-5p/SOX2 axis.

摘要

背景

非小细胞肺癌是全球癌症相关死亡的主要原因。长链非编码RNA MIR4435-2HG已被证明在多种癌症中发挥致癌作用。本研究旨在探讨MIR4435-2HG在非小细胞肺癌中的作用及调控机制。

方法

采用定量实时聚合酶链反应检测非小细胞肺癌细胞中MIR4435-2HG和SRY盒转录因子2。随后进行MIR4435-2HG和SRY盒转录因子2的功能获得或缺失实验。检测细胞增殖、凋亡、迁移、糖酵解和侵袭情况。构建裸鼠肿瘤模型，以确定MIR4435-2HG和SRY盒转录因子2在体内肿瘤细胞生长中的作用。此外，通过双荧光素酶报告基因实验分析MIR4435-2HG、miR-371a-5p和SRY盒转录因子2之间的相互作用。

结果

定量实时聚合酶链反应显示，非小细胞肺癌细胞中MIR4435-2HG和SRY盒转录因子2上调。强制过表达MIR4435-2HG导致细胞增殖、迁移、侵袭和糖酵解增加，并抑制细胞凋亡。过表达MIR4435-2HG促进SRY盒转录因子2表达和PI3K/Akt/mTOR通路激活。下调MIR4435-2HG在体外和体内均具有抗肿瘤作用。SRY盒转录因子2过表达大多逆转了MIR4435-2HG下调的抑制作用。机制研究表明，MIR4435-2HG作为一种竞争性内源性RNA，直接靶向并抑制miR-371a-5p。挽救实验表明，miR-371a-5p过表达或SRY盒转录因子2下调显著抑制MIR4435-2HG介导的致癌作用。