Abstract
Background
Lung cancer is the most common primary malignant tumor of the lung, and 85% of lung cancer is non-small cell lung cancer (NSCLC). The N6-methyladenosine (m6A) and long noncoding RNAs (lncRNAs) have been widely reported to participate in the development of non-small cell lung cancer.
Objective
However, the potential molecular mechanisms of m6A-regulated lncRNAs in NSCLC still need further investigation.
Methods
The expression levels and the role of lncRNA NEAT1 in NSCLC tissues or cells were measured by RT-qPCR, Western blot, cell counting kit 8 (CCK-8), flow cytometry assay. RNA immunoprecipitation (RIP) was used to measure the levels of m6A modification of NEAT1. Bioinformatics analysis and dual-luciferase reporter gene assay were detected the relationship between miR-361-3p and NEAT1/HMGA1. Mouse xenograft tumor models were established to confirm the effects of lncRNA NEAT1 in vivo.
Results
In this study, we verified whether m6A-modified lncRNA nuclear enriched abundant transcript 1 (NEAT1) is involved in NSCLC progression via miR-361-3p/HMGA1 axis. Firstly, we found that lncRNA NEAT1 was upregulated in NSCLC, and was associated with a poor survival in NSCLC patients. Methyltransferase like 3 (METTL3)-mediated m6A modification stabilized and upregulated NEAT1 expression. Next, function experiment indicated that depletion of METTL3 and NEAT1 induced cell apoptosis and inhibited cell proliferation, epithelial-mesenchymal transition (EMT). Likewise, in vivo experiments further supported the oncogenic role of NEAT1 in NSCLC. In addition, the molecular mechanism was uncovered in our study, and we found that lncRNA NEAT1 promoted the expression of high-mobility group AT-hook 1 (HMGA1) by sponging miR-361-3p and then promoted tumorigenesis of NSCLC.
Conclusion
In conclusion, our findings demonstrated that METTL3-mediated m6A modification accelerated NSCLC progression by regulating the NEAT1/miR-361-3p/HMGA1 axis, which provides important targets for the treatment of NSCLC.
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Data availability
The data in our study are available from the corresponding author upon reasonable request.
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Funding
This study was supported by the research grant from the Beijing Health Promotion Association (BJHPA) and China Guanghua Technology Foundation.
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Li Qi conceived the designed and wrote the manuscript, Yue Yin and Mengqi Sun contributed the data collection and performed the experiments. Yue Yin conducted data analysis. All authors reviewed and accepted the manuscript.
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All tissues samples were collected using protocols approved by the Ethics Committee of the Affiliated Second Hospital of Harbin Medical University. Written informed consent was signed by each patient or legal guardianship. All animal experiments were approved by the Animal Ethics Committee of the Second Affiliated Hospital of Harbin Medical University (SYDW2022-115), and complies with the NIH Guide for the Care and Use of Laboratory Animals.
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Qi, L., Yin, Y. & Sun, M. m6A-mediated lncRNA NEAT1 plays an oncogenic role in non-small cell lung cancer by upregulating the HMGA1 expression through binding miR-361-3p. Genes Genom 45, 1537–1547 (2023). https://doi.org/10.1007/s13258-023-01442-1
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DOI: https://doi.org/10.1007/s13258-023-01442-1