Yang Wuping, Zhou Jingcheng, Zhang Kenan, Li Lei, Xu Yawei, Ma Kaifang, Xie Haibiao, Cai Lin, Gong Yanqing, Gong Kan
Department of Urology, Peking University First Hospital, Beijing 100034, P.R. China.
Hereditary Kidney Cancer Research Center, Peking University First Hospital, Beijing 100034, P.R. China.
J Cancer. 2021 Mar 5;12(9):2702-2714. doi: 10.7150/jca.55113. eCollection 2021.
Accumulating evidence suggests that lncRNAs (long non-coding RNAs) function as oncogenes or tumor suppressor genes in ccRCC (clear cell renal cell carcinoma). Although VHL (Von Hippel-Lindau) gene inactivation is by far the most common carcinogenic driving event in ccRCC, the roles of VHL-related lncRNAs in ccRCC remain unknown. In this study, using RNA-seq and clinical data in TCGA-KIRC (the Cancer Genome Atlas-Kidney Renal Clear Cell Carcinoma), we identified VHL-related lncRNAs through WGCNA (Weighted Gene Co-expression Network Analysis), correlation analysis and catRAPID algorithm, and explored their clinical characteristics in ccRCC. Results showed that 10 lncRNAs (AC112220.2, AL391121.1, USP46-AS1, AL450326.1, MID1IP1-AS1, SUCLG2-AS1, RAP2C-AS1, FGD5-AS1, AC018647.2 and AC015922.2) were identified as VHL-related lncRNAs, and they were down-regulated in ccRCC tissues. Survival analysis results indicated that high expression groups of AC112220.2, AL391121.1, USP46-AS1, AL450326.1, SUCLG2-AS1, RAP2C-AS1, FGD5-AS1, AC018647.2 and AC015922.2 had significantly longer OS (Overall Survival) than their respective low expression groups. Meanwhile high AC112220.2, USP46-AS1, AL450326.1, SUCLG2-AS1, FGD5-AS1, AC018647.2 and AC015922.2 expression groups had remarkably longer DFS (Disease Free Survival) than their respective low expression groups. Besides, FGD5-AS1 and AL391121.1 expression were decreased in VHL mutant tissues compared with VHL non-mutant tissues. Moreover, high expression group of FGD5-AS1 had significantly longer OS and DFS than their respective low expression groups in VHL mutant ccRCC. In addition, we found that DNA hypermethylation may also play an important role in decreased FGD5-AS1 expression. Furthermore, we validated the expression of FGD5-AS1 in VHL mutant and non-mutant ccRCC tissues and cell lines. In conclusion, our results demonstrated that lncRNA FGD5-AS1 was significantly associated with VHL and can serve as a novel biomarker of ccRCC.
越来越多的证据表明，长链非编码RNA（lncRNAs）在透明细胞肾细胞癌（ccRCC）中作为癌基因或肿瘤抑制基因发挥作用。虽然VHL（冯·希佩尔-林道）基因失活是ccRCC中迄今为止最常见的致癌驱动事件，但VHL相关lncRNAs在ccRCC中的作用仍不清楚。在本研究中，我们利用癌症基因组图谱-肾透明细胞癌（TCGA-KIRC）中的RNA测序和临床数据，通过加权基因共表达网络分析（WGCNA）、相关性分析和catRAPID算法鉴定了VHL相关lncRNAs，并探讨了它们在ccRCC中的临床特征。结果显示，10个lncRNAs（AC112220.2、AL391121.1、USP46-AS1、AL450326.1、MID1IP1-AS1、SUCLG2-AS1、RAP2C-AS1、FGD5-AS1、AC018647.2和AC015922.2）被鉴定为VHL相关lncRNAs，且它们在ccRCC组织中表达下调。生存分析结果表明，AC112220.2、AL391121.1、USP46-AS1、AL450326.1、SUCLG2-AS1、RAP2C-AS1、FGD5-AS1、AC018647.2和AC015922.2的高表达组的总生存期（OS）显著长于各自的低表达组。同时，AC112220.2、USP46-AS1、AL450326.1、SUCLG2-AS1、FGD5-AS1、AC018647.2和AC015922.2的高表达组的无病生存期（DFS）明显长于各自的低表达组。此外，与VHL非突变组织相比，FGD5-AS1和AL391121.1在VHL突变组织中的表达降低。而且，在VHL突变的ccRCC中，FGD5-AS1的高表达组的OS和DFS显著长于各自的低表达组。此外，我们发现DNA高甲基化可能在FGD5-AS1表达降低中也起重要作用。此外，我们验证了FGD5-AS1在VHL突变和非突变的ccRCC组织及细胞系中的表达。总之，我们的结果表明lncRNA FGD5-AS1与VHL显著相关，可作为ccRCC的一种新型生物标志物。
