lncRNA ZNRD1-AS1 promotes malignant lung cell proliferation, migration, and angiogenesis via the miR-942/TNS1 axis and is positively regulated by the m <sup>6</sup>A reader YTHDC2

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Abstract

Rationale

Lung cancer is the most prevalent form of cancer and has a high mortality rate, making it a global public health concern. The N ⁶-methyladenosine (m ⁶A) modification is a highly dynamic and reversible process that is involved in a variety of essential biological processes. Using in vitro, in vivo, and multi-omics bioinformatics, the present study aims to determine the function and regulatory mechanisms of the long non-coding (lnc)RNA zinc ribbon domain-containing 1-antisense 1 (ZNRD1-AS1).

Methods

The RNAs that were bound to the m ⁶A ‘reader’ were identified using YTH domain-containing 2 (YTHDC2) RNA immunoprecipitation (RIP)-sequencing. Utilizing methylated RIP PCR/quantitative PCR, pull-down, and RNA stability assays, m ⁶A modification and ZNRD1-AS1 regulation were analyzed. Using bioinformatics, the expression levels and clinical significance of ZNRD1-AS1 in lung cancer were evaluated. Using fluorescent in situ hybridization and quantitative PCR assays, the subcellular location of ZNRD1-AS1 was determined. Using cell migration, proliferation, and angiogenesis assays, the biological function of ZNRD1-AS1 in lung cancer was determined. In addition, the tumor suppressor effect of ZNRD1-AS1 in vivo was validated using a xenograft animal model. Through bioinformatics analysis and in vitro assays, the downstream microRNAs (miRs) and competing endogenous RNAs were also predicted and validated.

Results

This study provided evidence that m ⁶A modification mediates YTHDC2-mediated downregulation of ZNRD1-AS1 in lung cancer and cigarette smoke-exposed cells. Low levels of ZNRD1-AS1 expression were linked to adverse clinicopathological characteristics, immune infiltration, and prognosis. ZNRD1-AS1 overexpression was shown to suppress lung cancer cell proliferation, migration, and angiogenesis in vitro and in vivo , and to reduce tumor growth in nude mice. ZNRD1-AS1 expression was shown to be controlled by treatment of cells with either the methylation inhibitor 3-Deazaadenosine or the demethylation inhibitor Meclofenamic. Furthermore, the miR-942/tensin 1 (TNS1) axis was demonstrated to be the downstream regulatory signaling pathway of ZNRD1-AS1.

Conclusions

ZNRD1-AS1 serves an important function and has clinical relevance in lung cancer. In addition, the findings suggested that m ⁶A modification could mediate the regulation of the ZNRD1-AS1/miR-942/TNS1 axis via the m ⁶A reader YTHDC2.

Graphical Abstract

Supplementary Information

The online version contains supplementary material available at 10.1186/s12943-022-01705-7.

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Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

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Taiwen Li, Jingxin Fu, Zexian Zeng … (2020)

Abstract Tumor progression and the efficacy of immunotherapy are strongly influenced by the composition and abundance of immune cells in the tumor microenvironment. Due to the limitations of direct measurement methods, computational algorithms are often used to infer immune cell composition from bulk tumor transcriptome profiles. These estimated tumor immune infiltrate populations have been associated with genomic and transcriptomic changes in the tumors, providing insight into tumor–immune interactions. However, such investigations on large-scale public data remain challenging. To lower the barriers for the analysis of complex tumor–immune interactions, we significantly improved our previous web platform TIMER. Instead of just using one algorithm, TIMER2.0 (http://timer.cistrome.org/) provides more robust estimation of immune infiltration levels for The Cancer Genome Atlas (TCGA) or user-provided tumor profiles using six state-of-the-art algorithms. TIMER2.0 provides four modules for investigating the associations between immune infiltrates and genetic or clinical features, and four modules for exploring cancer-related associations in the TCGA cohorts. Each module can generate a functional heatmap table, enabling the user to easily identify significant associations in multiple cancer types simultaneously. Overall, the TIMER2.0 web server provides comprehensive analysis and visualization functions of tumor infiltrating immune cells.

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Author and article information

Contributors

Rui Chen: chenruigood@126.com

Jianxiang Li:

ORCID: http://orcid.org/0000-0001-6674-7703

aljxcr@suda.edu.cn

Journal

Journal ID (nlm-ta): Mol Cancer

Journal ID (iso-abbrev): Mol Cancer

Title: Molecular Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-4598

Publication date (Electronic): 30 December 2022

Publication date PMC-release: 30 December 2022

Publication date Collection: 2022

Volume: 21

Electronic Location Identifier: 229

Affiliations

[1 ]GRID grid.263761.7, ISNI 0000 0001 0198 0694, School of Public Health, , Suzhou Medical College of Soochow University, ; Suzhou, 215123 Jiangsu China

[2 ]GRID grid.452666.5, ISNI 0000 0004 1762 8363, Department of Respiratory Medicine, , The Second Affiliated Hospital of Soochow University, ; Suzhou Jiangsu, 215004 China

Author information

Jianxiang Li http://orcid.org/0000-0001-6674-7703

Article

Publisher ID: 1705

DOI: 10.1186/s12943-022-01705-7

PMC ID: 9801573

PubMed ID: 36581942

SO-VID: 3dca543d-4e74-4046-86f6-8d20b1a3d7fb

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 16 October 2022

Date accepted : 20 December 2022

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 82070095

Award ID: 81573178

Funded by: Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases

Funded by: Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: lncrna znrd1-as1,cigarette smoke,lung cancer,m6a rna methylation,immune infiltration,mir-942,tns1

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: lncrna znrd1-as1, cigarette smoke, lung cancer, m6a rna methylation, immune infiltration, mir-942, tns1