Identification of a three-long noncoding RNA prognostic model involved competitive endogenous RNA in kidney renal clear cell carcinoma

Abstract

Background: Lone 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.Methods: 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) located in 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.Results: 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.Conclusion: 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 3 insight into the prognostic biomarkers and therapeutic targets of KIRC. BackgroundKidney Renal Clear Cell Carcinoma (KIRC), the most common and aggressive malignant subtype of renal cell carcinoma, has a poor prognosis and high mortality in an advanced stage due to the lack of useful biomarkers and treatments [1]. Currently, there is a multitude of established treatments for KIRC, such as surgical resection, nonspecific immune approach, targeted therapy against vascular endothelial growth factor, and novel immunotherapy agents. Despite these treatments, about 50% of KIRC patients develop metastases, and the 5-year survival rate of these patients is still lower than 10% [2]. Therefore, the identification of u...

Genome Instability-related Long Non-coding RNA in Clear Renal Cell Carcinoma Determined using Computational Biology

“…After a careful literature search, we found that the biological process of LINC00460 and LINC01234 in the GILncSig has not been reported to date. We found that the lncRNA LINC00460 was located on chromosome 13q33.2 and is a prognostic biomarker for esophageal squamous cell carcinoma [38] and renal carcinoma [22].…”

“…To determine the accuracy of clinical predictive models related to genome stability, we performed diagnostic test comparisons. Three recently published lncRNA signatures were involved in comparisons: the three-lncRNA signature derived from Zhang et al (Zhang Dan) [22], the four-lncRNA signature derived from Liu et al LiulncSig) [23] and an immune signature derived from Sun et al (SunlncSig) [24] using the same TCGA patient cohort. As shown in Figure 8, the AUC of overall survival for the GILncSig was 0.681, which was significantly higher than those of SunlncSig (AUC = 0.657) and LiulncSig (AUC = 0.656) (Figure 8).…”

Development of genomic instability-associated long non-coding RNA signature: a prognostic risk model of clear cell renal cell carcinoma

“…Coincidentally, Zhang D, et al researched on LINC00460 as well. When identifying a three-lncRNA prognostic model [41], they speculated LINC00460's competing endogenous feature for its overexpression in ccRCC but did not mention its potential genomic instability. Controversially, the mutation frequency and expression did not exhibit to be consistently differential when quantitative analyses were performed (Figure 5), probably due to the uncertain carcinogenic mechanism in ccRCC.…”

Identification of Autophagy-Related Long Non-Coding RNA Prognostic Signature for Clear Cell Renal Cell Carcinoma

“…Recently, AC026356.2 and MELTF-AS1 were identi ed as immune-related lncRNA and showed a signi cant relationship with KIRC prognosis [22]. Zhang et al established a lncRNA prognostic model based on LINC00460, MIAT, and LINC00443 from a competitive endogenous RNA regulatory network constructed in KIRC [23]. The function of HOTAIRM1 in KIRC was reported by Hamilton et al [24].…”