METTL3 promotes the progression of bladder cancer through the METTL3/IGF2BP3/MTA1/PI3K/AKT axis.

BACKGROUND

Bladder cancer (BCa) is a prevalent urinary tract malignancy with consistently high incidence and mortality. N6-methyladenosine (m6A), mainly catalyzed by methyltransferase-like 3 (METTL3), is a common internal mRNA modification. This study explores METTL3's role in BCa progression.

METHODS

The TCGA database was utilized for gene expression prediction, with qRT-PCR for validation. KM-plotter analyzed the correlation of metastasis-associated 1 (MTA1) with patient prognosis. Western blot evaluated protein expression. Cell viability, proliferation, apoptosis, and invasion were tested via MTT, EdU, flow cytometry, and transwell assays. Glucose consumption, lactate production, and ATP/ADP ratios were measured with specific kits. Gene expression correlations were predicted via TCGA, GEPIA, and ENCORI databases. The SRAMP website predicted gene methylation sites. The MeRIP assay determined gene m6A methylation levels. RIP assay confirmed gene interactions. Act D test evaluated mRNA stability. Mouse xenograft and pulmonary metastasis models validated findings in vivo, and IHC assay detected tumor gene expression.

RESULTS

MTA1 showed high expression in BCa tissues and cells, correlating with poor patient prognosis. Downregulation of MTA1 effectively suppressed BCa cell viability, proliferation, invasion, glycolysis, and promoted apoptosis. METTL3 was upregulated in BCa, and its knockdown reduced MTA1 expression, m6A methylation, and mRNA stability. Insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) mediated MTA1 m6A methylation, enhancing its expression and mRNA stability in BCa cells. METTL3 participated in mediating BCa progression by activating the PI3K/AKT pathway through MTA1. In vivo, METTL3 facilitated tumor growth and pulmonary metastasis through MTA1.

CONCLUSIONS

This study reveals that METTL3 facilitates BCa progression via MTA1-dependent partial activation of the IGF2BP3-PI3K/AKT axis, suggesting a potential therapeutic target.