Background: m6A-methyltransferase METTL3 and demethylase FTO regulate gene expression
by dynamically modifying RNA methylation. However, their clinical relevance in renal
Clear Cell Carcinoma (CCRCC) has not been well elucidated.
Objective: This study aims to investigate prognostic values of FTO and METTL3 mRNA and DNA
methylation, their differential expression and associations with chemokines and inflammation-related
genes in CCRCC.
Methods: Kaplan-Meier survival curves and multivariate cox regression were performed for survival
analyses, and random-effects meta-analysis was conducted for differential expression of FTO
and METTL3 in CCRCC.
Results: A significantly negative correlation was observed between mRNA and DNA methylation
for both FTO and METTL3. Survival analysis showed a superior survival in patients with either
high FTO mRNA or low DNA methylation, or low METTL3 mRNA or high DNA methylation.
The adjusted hazard ratios were 0.67 (95% CI: 0.49-0.91, p = 0.01) for high vs. low FTO mRNA,
2.17 (1.38-3.42, p = 0.0008) for high vs. low FTO DNA methylation, 1.97 (1.45-2.68, p < 0.0001)
for high vs. low METTL3 mRNA, and 0.49 (0.31-0.79, p = 0.003) for high vs. low METTL3 DNA
methylation, respectively. There was a significant interaction between FTO and METTL3 mRNA
levels (p = 0.024). Upregulation of FTO and METTL3 with 1.64 folds (95% CI: 1.43-1.89) and
1.17 folds (1.02-1.35), respectively, was observed in CCRCC vs. normal kidney tissues. FTO and
METTL3 mRNA showed opposite expressions of CD8+ T cell migration-related chemokines.
Conclusion: Dysregulated FTO and METTL3 may be involved in the disease development and progression,
affecting immune response in CCRCC. FTO and METTL3 expression and DNA methylation
are potential prognostic markers of CCRCC.