METTL3/IGF2BP2 mediates m6A methylation modification of SNRPA1 to promote tumor property of non-small cell lung cancer cells

Non-small cell lung Cancer (NSCLC) is a major cause of cancer-related deaths worldwide. One protein involved in RNA processing and splicing, SNRPA1, has been suggested to play a role in the pathogenesis of NSCLC. Therefore, investigating the regulatory mechanisms involving small nuclear ribonucleoprotein polypeptide A' (SNRPA1) in NSCLC could provide valuable insights into the disease progression. The study involved the analysis of SNRPA1, methyltransferase 3, n6-adenosine-methyltransferase complex catalytic subunit (METTL3), Insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) and twist family bHLH transcription factor 1 (TWIST1) expressions in lung tissues and normal lung tissues using data obtained from the TCGA, CPTAC, and/or ENCORI databases. The prognostic value of SNRPA1 in lung tissues was assessed through the Kaplan-Meier Plotter database and TCGA database. mRNA expression was quantified via qRT-PCR, while protein expression was evaluated using western blotting assay or IHC assay. Cell viability, proliferation, migration, and invasion were analyzed through various in vitro assays. The interaction between SNRPA1 and METTL3 or IGF2BP2 was studied using RIP assay, dual-luciferase reporter assay, and actinomycin D assay, while the association of SNRPA1 with TWIST was determined through Co-IP assay and CHX assay. The effects of METTL3 silencing and SNRPA1 overexpression on malignant growth of NSCLC cells were confirmed using a xenograft mouse model assay and a lung metastasis model. SNRPA1 expression was significantly upregulated in NSCLC tissues and cells. Depletion of SNRPA1 led to the inhibition of NSCLC cell proliferation, migration, and invasion. Additionally, METTL3 and IGF2BP2 were found to stabilize SNRPA1 mRNA expression through m6A methylation modification. SNRPA1 overexpression attenuated the effects induced by METTL3 knockdown on NSCLC cells in vitro. Furthermore, SNRPA1 was observed to interact with TWIST1 in NSCLC cells, and TWIST1 overexpression attenuated SNRPA1 knockdown-induced effects on the key malignant phenotypes. In vivo experiments showed that SNRPA1 overexpression rescued the effects of METTL3 depletion on the malignant growth of NSCLC cells. The findings of this study highlight the crucial role of the METTL3/IGF2BP2-SNRPA1-TWIST1 axis in promoting NSCLC development through m6A methylation modification. Targeting this pathway may offer novel therapeutic strategies for the treatment of NSCLC.

Graphical abstract: The METTL3/IGF2BP2-mediated m6A methylation modification of SNRPA1 binds to TWIST1 to promote NSCLC cell proliferation, migration, and invasion, ultimately leading to NSCLC progression.

Supplementary information: The online version contains supplementary material available at 10.1007/s10616-026-00924-w.

Cancer progression; METTL3; Non-small cell lung cancer; SNRPA1; TWIST1.