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METTL3 promotes the malignancy of non-small cell lung cancer by N6-methyladenosine modifying SFRP2

Cancer Gene Therapy volume 30, pages 1094–1104 (2023)Cite this article

Subjects

Abstract

This study aimed to investigate the roles of METTL3, a regulator of m6A, in NSCLC. RT-qPCR was applied to determine mRNA of m6A-associated genes and SFRP2, and western blot were used for ZEB1 and MMP9 protein expression. Total m6A level was measured using methylated RNA immunoprecipitation (MeRIP) assay, and RIP was used to access m6A level of SFRP2. Cellular behaviors were detected using CCK-8 and tranwell assays. Xenograft assays were conducted to further verify the roles of METTL3 and SFRP2 in NSCLC. The expression level of METTL3 was higher in NSCLC than normal controls. However, downregulation of METTL3 restrained the proliferation, migration and invasion of NSCLC cells. Enhanced expression of METTL3 caused the inverse consequences. Moreover, SFRP2 was found to be negatively regulated by METTL3. Intriguingly, the anti-tumor functions of METTL3 knockdown in the phenotype of NSCLC cells and xenograft mice were overturned by inhibition of SFRP2. Silencing METTL3 resulted in the enhanced stability of SFRP2. Finally, downregulation of SFRP2 induced by METTL3 activated the Wnt/β-catenin signaling pathway in NSCLC. METTL3 acted as an oncogene in the pathogenesis of NSCLC via suppressing SFRP2 to activate Wnt/β-catenin signaling pathway, indicating that METTL3 might be a promising predictor in NSCLC.

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Fig. 1: Highly expressed METTL3 is connected with diagnosis and poor prognosis in NSCLC.
Fig. 2: Knockdown of METTL3 alleviated the malignant traits of NSCLC cells.
Fig. 3: SFRP2 is a gene related to lung cancer which is negatively related with METTL3.
Fig. 4: METTL3 can modify SFRP2 by m6A methylation to weaken the stability of SFRP2.
Fig. 5: Suppression of SFRP2 abolished the potency of METTL3 knockdown in NSCLC cell proliferation, migration and invasion.
Fig. 6: Silencing SFRP2 abolished the potency of METTL3 knockdown in tumor growth of NSCLC in vivo.
Fig. 7: SFRP2 participates in the Wnt/β-catenin signaling pathway in NSCLC.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This study was supported by Study on the safety and efficacy of transbronchial or percutaneous one-stop microwave ablation in the treatment of pulmonary nodules(GWJJ2021100304).

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Author notes

  1. These authors contributed equally: Shu Zhao, Peng Song, Gang Zhou.

Authors and Affiliations

  1. Medical School of Chinese PLA, Chinese PLA General Hospital, 100853, Beijing, China

    Shu Zhao

  2. Department of Medical Oncology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, 100853, Beijing, China

    Shu Zhao, Peng Song, Gang Zhou & Dong Zhang

  3. Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, 100071, Beijing, China

    Yi Hu

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Contributions

PS and GZ conceived the study; DZ conducted the experiments; YH analyzed the data; SZ wrote the manuscript; all the authors read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Dong Zhang or Yi Hu.

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The authors declare no competing interests.

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This study protocol was approved by the Ethics Committee of Chinese PLA General Hospital. All manipulations on mice conformed to the standards of the Institutional Animal Care and Utilization Committee of Chinese PLA General Hospital.

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Zhao, S., Song, P., Zhou, G. et al. METTL3 promotes the malignancy of non-small cell lung cancer by N6-methyladenosine modifying SFRP2. Cancer Gene Ther 30, 1094–1104 (2023). https://doi.org/10.1038/s41417-023-00614-1

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