Mu Zhongyi, Dong Dan, Sun Mingli, Li Liwen, Wei Ning, Hu Bin
Department of Urology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China.
Department of Pathophysiology, College of Basic Medical Science, China Medical University, Shenyang, China.
Front Oncol. 2020 Sep 23;10:1566. doi: 10.3389/fonc.2020.01566. eCollection 2020.
m6A, the main form of mRNA modification, participates in regulating multiple normal and pathological biological events, especially in tumorigenesis. However, there is little known about the association of m6A-related genes with prognosis of clear cell renal cell cancer (ccRCC). Therefore, the prognostic value of m6A-related genes was investigated using Kaplan-Meier curves of overall survival (OS) with the log-rank test and Cox regression analysis. The differential expression of YTHDF2 mRNA in ccRCC and tumor-adjacent normal tissues and associated with clinicopathological characteristics was also analyzed. The alteration of cancer signaling pathways was screened by Gene Set Enrichment Analysis (GSEA). Univariate analysis showed that 15 m6A-related genes (including YTHDF2) were closely related to prognosis. Multivariate analysis further confirmed that YTHDF2 could serve as an independent prognostic factor for the OS of ccRCC patients ( < 0.001). Low-level expression of YTHDF2 had poor prognosis in ccRCC patients with lower tumor-node-metastasis (TNM) stage, age > 61, non-distant metastasis, non-lymph node metastasis, female gender, and higher histological grade ( < 0.05). Moreover, YTHDF2 expression in ccRCC tissues ( = 529) is significantly lower than that of tumor-adjacent normal tissues ( = 72, = 0.0086). Furthermore, GSEA demonstrated that AKT/mTOR/GSK3 pathway, EIF4 pathway, CHREBP2 pathway, MET pathway, NFAT pathway, FAS pathway, EDG1 pathway, and CTCF pathway are altered in tumors with high YTHDF2 expression. Taken together, our results demonstrated that YTHDF2 (an m6A-related gene) could serve as a potential prognostic biomarker of ccRCC, and targeting epigenetic modification may be a novel therapeutic strategy for the treatment of ccRCC.
m6A是mRNA修饰的主要形式，参与调节多种正常和病理生物学事件，尤其是在肿瘤发生过程中。然而，关于m6A相关基因与透明细胞肾细胞癌（ccRCC）预后的关联知之甚少。因此，使用总生存（OS）的Kaplan-Meier曲线结合对数秩检验和Cox回归分析来研究m6A相关基因的预后价值。还分析了YTHDF2 mRNA在ccRCC组织和癌旁正常组织中的差异表达及其与临床病理特征的相关性。通过基因集富集分析（GSEA）筛选癌症信号通路的改变。单因素分析显示15个m6A相关基因（包括YTHDF2）与预后密切相关。多因素分析进一步证实YTHDF2可作为ccRCC患者OS的独立预后因素（P<0.001）。YTHDF2低表达在肿瘤-淋巴结-转移（TNM）分期较低、年龄>61岁、无远处转移、无淋巴结转移、女性以及组织学分级较高的ccRCC患者中预后较差（P<0.05）。此外，YTHDF2在ccRCC组织（n=529）中的表达明显低于癌旁正常组织（n=72，P=0.0086）。此外，GSEA表明在YTHDF2高表达的肿瘤中，AKT/mTOR/GSK3通路、EIF4通路、CHREBP2通路、MET通路、NFAT通路、FAS通路、EDG1通路和CTCF通路发生了改变。综上所述，我们的结果表明YTHDF2（一个m6A相关基因）可作为ccRCC潜在的预后生物标志物，靶向表观遗传修饰可能是治疗ccRCC的一种新的治疗策略。
