Wei Jingsun, Qian Yucheng, Tang Yang, Ge Xiaoxu, Jiang Kai, Fang Yimin, Fu Dongliang, Kong Xiangxing, Xiao Qian, Ding Kefeng
Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.
Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China.
Onco Targets Ther. 2021 Jan 14;14:413-426. doi: 10.2147/OTT.S288663. eCollection 2021.
N6-methyladenosine (m6A) modifications represent one of the most common methylation modifications, and they are mediated by m6A RNA methylation regulators. However, their functions in renal cell carcinoma (RCC) are not completely understood. The aim of this study was to investigate the effects of the regulators in RCC.
The expression levels of the 13 main m6A RNA methylation regulators in RCC were detected and consensus clustering was performed to explore their relationships with RCC. Thereafter, a risk signature based on the regulators was established. This risk model was fully verified by conducting prognostic analyses using two datasets (The Cancer Genome Atlas [TCGA] and Gene Expression Omnibus [GEO] datasets) and a ROC curve analysis.
Of the 13 main m6A regulators, six were significantly upregulated and four were significantly downregulated in 893 RCC cases compared to 128 normal controls in the TCGA database. Consensus clustering based on the regulators identified two clusters of RCC cases, which were significantly associated with a pathological characteristic (T status). Thus, these results indicated that m6A RNA methylation regulators were associated with RCC. Thereafter, a risk model involving two of the regulators (METTL14 and WTAP) was established. The alterations in the mRNA and protein expression levels of these two regulators were further confirmed based on Human Protein Atlas data and real-time PCR in RCC and normal cell lines. The results indicated that the risk model may serve as an independent prognostic marker of overall survival, and it was also associated with clinicopathological characteristics (T status, M status, pathological stage, and gender) in RCC.
Collectively, the results of this study indicated that the risk model (based on two m6A RNA methylation regulators) may serve as an independent prognostic indicator of RCC, which may aid further investigation into m6A RNA modification in RCC.
N6-甲基腺苷（m6A）修饰是最常见的甲基化修饰之一，由m6A RNA甲基化调节因子介导。然而，它们在肾细胞癌（RCC）中的功能尚未完全明确。本研究旨在探讨这些调节因子在RCC中的作用。
检测RCC中13种主要m6A RNA甲基化调节因子的表达水平，并进行一致性聚类以探讨它们与RCC的关系。此后，基于这些调节因子建立了一个风险特征模型。通过使用两个数据集（癌症基因组图谱[TCGA]和基因表达综合数据库[GEO]数据集）进行预后分析和ROC曲线分析，对该风险模型进行了全面验证。
在TCGA数据库中，与128例正常对照相比，893例RCC病例中13种主要m6A调节因子中有6种显著上调，4种显著下调。基于这些调节因子的一致性聚类识别出RCC病例的两个聚类，它们与一种病理特征（T分期）显著相关。因此，这些结果表明m6A RNA甲基化调节因子与RCC相关。此后，建立了一个涉及其中两个调节因子（METTL14和WTAP）的风险模型。基于人类蛋白质图谱数据以及RCC和正常细胞系中的实时PCR，进一步证实了这两个调节因子的mRNA和蛋白质表达水平的变化。结果表明，该风险模型可能作为总生存期的独立预后标志物，并且还与RCC的临床病理特征（T分期、M分期、病理分期和性别）相关。
总体而言，本研究结果表明风险模型（基于两种m6A RNA甲基化调节因子）可能作为RCC的独立预后指标，这可能有助于进一步研究RCC中的m6A RNA修饰。
