Fan Guobin, Wu Dejun, Chen Huaping, Wen Zhi, Liao Linhui, He Shuming, Yang Jie
Department of Urology, Wanning People's Hospital, Wanning, China.
Department of Urology, Hainan West Central Hospital, Danzhou, China.
Environ Toxicol. 2024 Feb;39(2):626-642. doi: 10.1002/tox.23920. Epub 2023 Aug 9.
As one of the most common messenger ribonucleic acid modifications in eukaryotic organisms, N6-methyladenosine (m6A) is involved in a wide variety of biological functions. The imbalance of m6A RNA modification may be linked to cancer and other disorders, according to a growing body of studies. Its effects on clear cell renal cell carcinoma (KIRC) have not been well discussed, though. Here, we acquired the expression patterns of 23 important regulators of m6A RNA modification and assess how they might fare in KIRC. We observed that 17 major m6A RNA modification regulatory factors had a substantial predictive influence on KIRC. Using the "ConsensusCluster" program, we defined two groupings (Cluster 1 and Cluster 2) depending on the expression of the aforementioned 17 key m6A RNA methylation regulators. The Cluster 2 has a less favorable outcome and is strongly related with a lesser immune microenvironment, according to the findings. We also developed a strong risk profile for three m6A RNA modifiers (METTL14, YTHDF1, and LRPPRC) using multivariate Cox regression analysis. According to further research, the aforementioned risk profile could serve as an independent predicting factor for KIRC, and the chemotherapy response sensitivity was analyzed between two risk groups. Moreover, to effectively forecast the future outlook of KIRC clients, we established a novel prognostic approach according to gender, age, histopathological level, clinical stage, and risk score. Finally, the function of hub gene METTL14 was validated by cell proliferation and subcutaneous graft tumor in mice. In conclusion, we discovered that m6A RNA modifiers play an important role in controlling KIRC and created a viable risk profile as a marker of prediction for KIRC clients.
作为真核生物中最常见的信使核糖核酸修饰之一，N6-甲基腺苷（m6A）参与了多种生物学功能。越来越多的研究表明，m6A RNA修饰的失衡可能与癌症和其他疾病有关。不过，其对肾透明细胞癌（KIRC）的影响尚未得到充分讨论。在此，我们获取了23个m6A RNA修饰重要调节因子的表达模式，并评估它们在KIRC中的表现。我们观察到17个主要的m6A RNA修饰调节因子对KIRC具有显著的预测影响。使用“ConsensusCluster”程序，我们根据上述17个关键m6A RNA甲基化调节因子的表达定义了两个分组（簇1和簇2）。结果显示，簇2的预后较差，且与较弱的免疫微环境密切相关。我们还使用多变量Cox回归分析为三个m6A RNA修饰因子（METTL14、YTHDF1和LRPPRC）建立了一个强大的风险模型。进一步研究表明，上述风险模型可作为KIRC的独立预测因子，并分析了两个风险组之间的化疗反应敏感性。此外，为了有效预测KIRC患者的未来预后，我们根据性别、年龄、组织病理学分级、临床分期和风险评分建立了一种新的预后方法。最后，通过细胞增殖和小鼠皮下移植瘤实验验证了枢纽基因METTL14的功能。总之，我们发现m6A RNA修饰因子在控制KIRC中起着重要作用，并创建了一个可行的风险模型作为KIRC患者的预测标志物。
