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

Overview

Journal SAGE Open Med

Publisher Sage Publications

Specialty General Medicine

Date 2024 Nov 11

PMID 39526092

Authors

Jin Yang

Yu Su

Yuchen Wang

Kun Gao

Chuang Li

Mengmeng Li

Affiliations

Soon will be listed here.

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.

References

Fassl A, Geng Y, Sicinski P . CDK4 and CDK6 kinases: From basic science to cancer therapy. Science. 2022; 375(6577):eabc1495. PMC: 9048628. DOI: 10.1126/science.abc1495. View

Genova C, Marconi S, Chiorino G, Guana F, Ostano P, Santamaria S . Extracellular vesicles miR-574-5p and miR-181a-5p as prognostic markers in NSCLC patients treated with nivolumab. Clin Exp Med. 2024; 24(1):182. PMC: 11303437. DOI: 10.1007/s10238-024-01427-8. View

Herman A, Tsitsipatis D, Gorospe M . Integrated lncRNA function upon genomic and epigenomic regulation. Mol Cell. 2022; 82(12):2252-2266. PMC: 9219586. DOI: 10.1016/j.molcel.2022.05.027. View

Lin S, Li Y, Wang D, Huang C, Marino D, Bollt O . Fascin promotes lung cancer growth and metastasis by enhancing glycolysis and PFKFB3 expression. Cancer Lett. 2021; 518:230-242. PMC: 8355190. DOI: 10.1016/j.canlet.2021.07.025. View

OLeary K, Shia A, Schmid P . Epigenetic Regulation of EMT in Non-Small Cell Lung Cancer. Curr Cancer Drug Targets. 2017; 18(1):89-96. DOI: 10.2174/1568009617666170203162556. View

Chandrashekar D, Karthikeyan S, Korla P, Patel H, Shovon A, Athar M . UALCAN: An update to the integrated cancer data analysis platform. Neoplasia. 2022; 25:18-27. PMC: 8788199. DOI: 10.1016/j.neo.2022.01.001. View

Lv Z, Qiu X, Jin P, Li Z, Zhang Y, Lv L . MiR-371a-5p Positively Associates with Hepatocellular Carcinoma Malignancy but Sensitizes Cancer Cells to Oxaliplatin by Suppressing BECN1-Dependent Autophagy. Life (Basel). 2022; 12(10). PMC: 9604925. DOI: 10.3390/life12101651. View

Wang X, Chen Y, Wang X, Tian H, Wang Y, Jin J . Stem Cell Factor SOX2 Confers Ferroptosis Resistance in Lung Cancer via Upregulation of SLC7A11. Cancer Res. 2021; 81(20):5217-5229. PMC: 8530936. DOI: 10.1158/0008-5472.CAN-21-0567. View

Henrique R, Santos A, Pereira M, Santos N, Pereira G, Cabral Filho P . Emerging trends on the uptake of fluorescent probes based on glucose analogs by cancer cells: From basic studies to therapeutics. Life Sci. 2024; 355:122978. DOI: 10.1016/j.lfs.2024.122978. View

10.

Xu H, Ma H, Zha L, Li Q, Pan H, Zhang L . Engineered exosomes transporting the lncRNA, SVIL-AS1, inhibit the progression of lung cancer via targeting miR-21-5p. Am J Cancer Res. 2024; 14(7):3335-3347. PMC: 11301303. DOI: 10.62347/YRJK5888. View

11.

Ramezani M, Shamsabadi F, Shahbazi M . Harnessing the TP53INP1/TP53I3 axis for inhibition of colorectal cancer cell proliferation through MEG3 and Linc-ROR Co-expression. Heliyon. 2024; 10(14):e34075. PMC: 11301216. DOI: 10.1016/j.heliyon.2024.e34075. View

12.

Novak D, Huser L, Elton J, Umansky V, Altevogt P, Utikal J . SOX2 in development and cancer biology. Semin Cancer Biol. 2019; 67(Pt 1):74-82. DOI: 10.1016/j.semcancer.2019.08.007. View

13.

Yu F, Zhao X, Li M, Meng M . SLITRK6 promotes the progression of lung adenocarcinoma by regulating PI3K/AKT/mTOR signaling and Warburg effect. Apoptosis. 2023; 28(7-8):1216-1225. DOI: 10.1007/s10495-023-01838-0. View

14.

Chelakkot C, Chelakkot V, Shin Y, Song K . Modulating Glycolysis to Improve Cancer Therapy. Int J Mol Sci. 2023; 24(3). PMC: 9916680. DOI: 10.3390/ijms24032606. View

15.

Bai P, Hou P, Kong Y . Hepatitis B virus promotes proliferation and metastasis in male Chinese hepatocellular carcinoma patients through the LEF-1/miR-371a-5p/SRCIN1/pleiotrophin/Slug pathway. Exp Cell Res. 2018; 370(1):174-188. DOI: 10.1016/j.yexcr.2018.06.020. View

16.

Xia Y, Wu Y, Liu B, Wang P, Chen Y . Downregulation of miR-638 promotes invasion and proliferation by regulating SOX2 and induces EMT in NSCLC. FEBS Lett. 2014; 588(14):2238-45. DOI: 10.1016/j.febslet.2014.05.002. View

17.

Bray F, Laversanne M, Sung H, Ferlay J, Siegel R, Soerjomataram I . Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024; 74(3):229-263. DOI: 10.3322/caac.21834. View

18.

Zafra J, Onieva J, Oliver J, Garrido-Barros M, Gonzalez-Hernandez A, Martinez-Galvez B . Novel Blood Biomarkers for Response Prediction and Monitoring of Stereotactic Ablative Radiotherapy and Immunotherapy in Metastatic Oligoprogressive Lung Cancer. Int J Mol Sci. 2024; 25(8). PMC: 11050102. DOI: 10.3390/ijms25084533. View

19.

Chen Z, Guan D, Zhu Q, Wang Z, Han F, Zhou W . Biological Roles and Pathogenic Mechanisms of LncRNA MIR4435-2HG in Cancer: A Comprehensive Review. Curr Issues Mol Biol. 2023; 45(11):8864-8881. PMC: 10670187. DOI: 10.3390/cimb45110556. View

20.

Ghasemian M, Rajabibazl M, Sahebi U, Sadeghi S, Maleki R, Hashemnia V . Long non-coding RNA MIR4435-2HG: a key molecule in progression of cancer and non-cancerous disorders. Cancer Cell Int. 2022; 22(1):215. PMC: 9205143. DOI: 10.1186/s12935-022-02633-8. View