A cluster of long non-coding RNAs exhibit diagnostic and prognostic values in renal cell carcinoma

Abstract

Kidney cancer ranked in the top 10 for both men and women in the estimated numbers of new cancer cases in the United States in 2018. Targeted therapies have recently been administered to patients with clear cell renal cell carcinoma (ccRCC), but the overall survival of patients at the terminal stage of the disease has not been as good as expected. It is therefore necessary to uncover efficient biomarkers for early diagnosis, and to clarify the molecular mechanisms underlying ccRCC progression and metastasis. Increased evidence has shown that long non-coding RNAs (lncRNAs) play important roles during tumor progression. In this study, 10 candidate lncRNAs with diagnostic and prognostic values in ccRCC were identified: IGFL2-AS1, AC023043.1, AP000439.2, AC124854.1, AL355102.4, TMEM246-AS1, AL133467.3, ZNF582-AS1, LINC01510 and PSMG3-AS1. Enrichment analysis revealed metabolic and functional pathways, which may be closely associated with kidney cancer tumorigenesis. Six representative processes were summarized, namely glycolysis, amino acid metabolism, lipid synthesis, reductive carboxylation, nucleotide metabolism, transmembrane transport and signal transduction. In combination, the present results provided prognostic and diagnostic biomarkers for ccRCC and might pave the way for targeted intervention and molecular therapies in the future.

Keywords: biomarkers; long non-coding RNA; metabolism; renal cell carcinoma.

Figure 1

Identification of differentially expressed lncRNAs in clear cell renal cell carcinoma. (A) Flow chart of study design. (B) Hierarchical clustering heatmap analysis of 12,727 lncRNAs with 54 paired samples from the TANRIC database. (C–M) Paired student’s t-test of candidate lncRNA relative expression between 54 paired normal and tumor samples. lncRNAs, long non-coding RNAs.

Figure 2

Candidate lncRNAs acts as potentially prognostic biomarkers for clear cell renal cell carcinoma. (A–D) Upregulated lncRNAs exhibited statistically significant difference between relative high gene expression and low expression in DFS. (E–H) Upregulated lncRNAs exhibited statistical difference in OS. (I–O) Downregulated lncRNAs exhibited statistical difference in DFS. (P–V) Downregulated lncRNAs exhibited statistical difference in OS. lncRNAs, long non-coding RNAs.

Figure 3

Assessment of correlation between candidate lncRNAs and clinicopathological characteristics. (A) Schematic diagram of four subgroups from 11 candidate lncRNAs. (B–L) Relative expression level comparison of each lncRNA in different characteristic subgroups (age, gender, T, N, M, grade and stage). *P<0.05, **P<0.01, ***P<0.001 and ****P<0.0001. lncRNAs, long non-coding RNAs.

Figure 4

LncRNAs play a diagnostic role in patients with clear cell renal cell carcinoma. (A–J) ROC curve analysis was performed to differentiate kidney cancer patients from healthy individuals, according to lncRNA expression. (K–R) Diagnostic accuracy was improved after combing AP000439.2 with previously reported RCC biomarkers. lncRNAs, long non-coding RNAs; ROC, receiver operating characteristic curve; RCC, renal cell carcinoma.

Figure 5

Potentially functional roles of candidate lncRNAs participating in ccRCC tumorigenesis. (A–B) Relative expression of lncRNAs was verified in cell lines by RT-qPCR. (C–F) Four modules of protein-protein interaction networks. (G–J) Intersections of these modules with respect to biological process, molecular function, and KEGG and Reactome pathways. (K) Potential mechanistic schematic diagram of the role of candidate lncRNAs in kidney cancer tumorigenesis. Each experiment was performed at least three times and data are presented as the mean ± SEM. P<0.05 was considered to indicate a statistically significant difference. *P<0.05, **P<0.01, ***P<0.001 and ****P<0.0001. lncRNAs, long non-coding RNA.