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.

背景：m6A-甲基转移酶 METTL3 和去甲基化酶 FTO 通过动态修饰 RNA 甲基化来调节基因表达。然而，它们在肾透明细胞癌（CCRCC）中的临床相关性尚未得到很好的阐明。

目的：本研究旨在探讨 FTO 和 METTL3 mRNA 和 DNA 甲基化的预后价值、它们的差异表达以及与 CCRCC 中趋化因子和炎症相关基因的关联。

方法：采用Kaplan-Meier生存曲线和多变量cox回归进行生存分析，对CCRCC中FTO和METTL3的差异表达进行随机效应荟萃分析。

结果：FTO 和 METTL3 的 mRNA 和 DNA 甲基化呈显着负相关。生存分析显示，高 FTO mRNA 或低 DNA 甲基化，或低 METTL3 mRNA 或高 DNA 甲基化的患者生存率更高。调整后的风险比为 0.67（95% CI：0.49-0.91，p = 0.01），高与低 FTO mRNA，高与低 FTO DNA 甲基化为 2.17（1.38-3.42，p = 0.0008），1.97（1.45- 2.68, p < 0.0001) 用于高与低 METTL3 mRNA，0.49 (0.31-0.79, p = 0.003) 用于高与低 METTL3 DNA 甲基化。FTO 和 METTL3 mRNA 水平之间存在显着的相互作用 (p = 0.024)。在 CCRCC 与正常肾组织中分别观察到 FTO 和 METTL3 上调 1.64 倍 (95% CI: 1.43-1.89) 和 1.17 倍 (1.02-1.35)。

结论：FTO和METTL3失调可能参与了CCRCC疾病的发生发展，影响免疫反应。FTO 和 METTL3 表达和 DNA 甲基化是 CCRCC 的潜在预后标志物。