Zhang Di, Zeng Song, Hu Xiaopeng
Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8 GongTi South Road, 100020 Beijing, China.
Institute of Urology, Capital Medical University, Beijing, China.
Cancer Cell Int. 2020 Jul 17;20:319. doi: 10.1186/s12935-020-01423-4. eCollection 2020.
Long noncoding RNA (lncRNA) is generally identified as competing endogenous RNA (ceRNA) that plays a vital role in the pathogenesis of kidney renal clear cell carcinoma (KIRC), the most common subtype of renal cell carcinoma with poor prognosis and unclear pathogenesis. This study established a novel ceRNA network and thus identified a three-lncRNA prognostic model in KIRC patients.
Differentially expressed genes (DEGs) were screened out from The Cancer Genome Atlas (TCGA) database. The lncATLAS was applied to determine the differentially expressed lncRNAs (DElncRNAs) of the cytoplasm. The miRcode, miRDB, miRTarBase, and TargetScan databases were utilized to predict the interactions of DElncRNAs, DEmiRNAs, and DEmRNAs. Cytoscape was used to construct the ceRNA network. Then, a lncRNA prognostic model (LPM) was constructed based on ceRNA-related lncRNA that was significantly related to overall survival (OS), and its predictive ability was evaluated. Moreover, an LPM-based nomogram model was constructed. The significantly different expression of genes in the LPM was validated in an independent clinical cohort (N = 21) by quantitative RT-PCR.
A novel ceRNA regulatory network, including 73 lncRNAs, 8 miRNAs, and 21 mRNAs was constructed. Functional enrichment analysis indicated that integral components of membrane and PI3K-Akt signaling pathway represented the most significant GO terms and pathway, respectively. The LPM established based on three lncRNAs (MIAT, LINC00460, and LINC00443) of great prognostic value from the ceRNA network was proven to be independent of conventional clinical parameters to differentiate patients with low or high risk of poor survival, with the AUC of 1-, 5- and 10-year OS were 0.723, 0.714 and 0.826 respectively. Furthermore, the nomogram showed a better predictive value in KIRC patients than individual prognostic parameters. The expression of MIAT and LINC00460 was significantly upregulated in the KIRC samples, while the expression of LINC00443 was significantly downregulated compared with the adjacent normal samples in the clinical cohort, TCGA, and GTEx.
This LPM based on three-lncRNA could serve as an independent prognostic factor with a tremendous predictive ability for KIRC patients, and the identified novel ceRNA network may provide insight into the prognostic biomarkers and therapeutic targets of KIRC.
长链非编码RNA（lncRNA）通常被鉴定为竞争性内源性RNA（ceRNA），在肾透明细胞癌（KIRC）的发病机制中起重要作用。KIRC是肾细胞癌最常见的亚型，预后较差且发病机制尚不清楚。本研究建立了一个新的ceRNA网络，从而在KIRC患者中鉴定出一个三lncRNA预后模型。
从癌症基因组图谱（TCGA）数据库中筛选出差异表达基因（DEG）。应用lncATLAS确定细胞质中差异表达的lncRNA（DElncRNA）。利用miRcode、miRDB、miRTarBase和TargetScan数据库预测DElncRNA、DEmiRNA和DEmRNA之间的相互作用。使用Cytoscape构建ceRNA网络。然后，基于与总生存期（OS）显著相关的ceRNA相关lncRNA构建lncRNA预后模型（LPM），并评估其预测能力。此外，构建了基于LPM的列线图模型。通过定量RT-PCR在一个独立的临床队列（N = 21）中验证LPM中基因的显著差异表达。
构建了一个新的ceRNA调控网络，包括73个lncRNA、8个miRNA和21个mRNA。功能富集分析表明，膜的整合成分和PI3K-Akt信号通路分别代表最显著的GO术语和通路。基于ceRNA网络中具有重要预后价值的三个lncRNA（MIAT、LINC00460和LINC00443）建立的LPM被证明独立于传统临床参数，可区分生存不良风险低或高的患者，1年、5年和10年总生存期的AUC分别为0.723、0.714和0.826。此外，列线图在KIRC患者中的预测价值优于个体预后参数。在临床队列、TCGA和GTEx中，与相邻正常样本相比，KIRC样本中MIAT和LINC00460的表达显著上调，而LINC00443的表达显著下调。
基于三个lncRNA的LPM可作为KIRC患者的独立预后因素，具有强大的预测能力，并且所鉴定的新ceRNA网络可能为KIRC的预后生物标志物和治疗靶点提供见解。
