2. Academic Validation
  3. Overexpression of METTL3 in lung cancer cells inhibits radiation-induced bystander effect

Overexpression of METTL3 in lung cancer cells inhibits radiation-induced bystander effect

  • Biochem Biophys Res Commun. 2025 May 1:761:151714. doi: 10.1016/j.bbrc.2025.151714.
Yong Zhang 1,  Rongrong Tian 1,  Xudong Feng 1,  Bin Xiao 1,  Qi Yue 1,  Jinling Wei 2,  Li Wang 3
Affiliations

Affiliations

  • 1 The First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Kunming, 650032, China.
  • 2 The First People's Hospital of Yunnan Province, Kunming, 650032, Yunnan, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China.
  • 3 The First People's Hospital of Yunnan Province, Kunming, 650032, Yunnan, China; The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China. Electronic address: [email protected].
PMID: 40184791 DOI: 10.1016/j.bbrc.2025.151714
Abstract

Background: Radiation-induced bystander effects (RIBE) increase the complexity of radiation therapy (RT). m6A modification is implicated in ionizing radiation damage. This study aims to investigate the RIBE and the mechanism after promoting m6A modification.

Methods: Lung adenocarcinoma cells were treated to simulate a hypoxic and 0.5 Gy RT environment. The expression levels of METTL3, METTL14, and YTDHF2 were quantified by RT-qPCR. Paracellular clonogenicity and the expression of 53BP1 and γ-H2AX were assessed by immunofluorescence. The proliferative rate was evaluated by CCK-8. Probes were employed to measure ROS levels. Micronucleus formation was evaluated microscopically. m6A-mRNA/lncRNA microarrays, MERIP-PCR, RT-qPCR, and ELISA were utilized to assess m6A modification levels and the expression of inflammatory factors.

Results: m6A modification levels were significantly diminished under hypoxic, low-dose irradiation conditions. The overexpression of METTL3 in irradiated Cancer cells resulted in increased clonogenicity and proliferation of paracellular cells, suppressed the rate of micronucleus formation, and reduced DNA damage by modulating the inflammatory response. m6A-mRNA/lncRNA microarray analyses revealed a higher correlation of inflammatory molecules NF-κB and TRAF6. Further analysis demonstrated that the m6A modification levels of inflammation-related factors such as IL-6, TLR4, NF-κB2, and TRAF6 were significantly up-regulated, while their mRNA expression levels were notably decreased. Additionally, the expression of IL-10 and TGF-β was significantly reduced, with no significant changes observed in IL-1 expression.

Conclusion: The overexpression of METTL3 facilitated m6A modification and mitigated the inflammatory response, thereby promoting paracellular cloning and proliferation, inhibiting micronucleus formation, alleviating DNA damage, and achieving the objective of suppression of RIBE.

Keywords

Inflammation; Low-dose ionizing radiation; Lung cancer; Radiation therapy; Radiation-induced bystander effect; m6A modification.

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