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Prognostic Signatures for Renal Cancer As Identified by Long Non-Coding and Mirna Competing Endogenous Network Analysis

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Prognostic Signatures for Renal Cancer As Identified by Long Non-Coding and Mirna Competing Endogenous Network Analysis ONCOLOGY REPORTS 40: 959-967, 2018 Prognostic signatures for renal cancer as identified by long non-coding and miRNA competing endogenous network analysis HONGWEI GAO*, XUANRONG CHEN*, ZHIQUN SHANG and YUANJIE NIU Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China Received December 13, 2017; Accepted May 31, 2018 DOI: 10.3892/or.2018.6476 Abstract. Long non-coding RNAs (lncRNAs) make up a regulatory mechanisms mediated by lncRNAs in the patho- significant portion of transcripts that are not translated into genesis of renal cell carcinoma. proteins and lncRNAs were previously thought to be tran- scriptional noise. Recently, there has been increased interest Introduction in lncRNAs due to their diverse functions in human cancers. At present, lncRNAs are considered to be the main component Worldwide, renal cell carcinoma (RCC) accounts for ~90% of the competing endogenous RNA (ceRNA) network due of all kidney neoplasms and 2-3% of adult malignant tumors, to their regulatory role in protein-coding gene expression by and it is the ninth most common cancer (1-3). RCC leads to a acting as microRNA (miRNA) sponges. However, the function considerable mortality rate, which is ~100,000 patients a year, of the lncRNA-mediated ceRNA network in renal cell carci- and the morbidity and mortality rates are increasing at a rate noma remains unknown. To examine the specific mechanism, of 2-3% per decade (4). There were ~63,920 newly diagnosed we compared the expression profiles of mRNAs, lncRNAs, cases of RCC in the US in 2014 (5). The treatment of meta- and miRNAs between renal cell carcinoma tissues and non- static RCC has improved in the past few decades. Although tumor normal tissues using the Gene Expression Omnibus cytoreductive nephrectomy is effective for the treatment of database. As a result, 5 lncRNAs were identified as aberrantly early and local RCC, ~30% of patients suffer from metastatic expressed and significantly correlated with the tumorigenesis disease after surgery. In addition, other therapeutic methods, and/or progression of renal cell carcinoma with the threshold such as immunotherapy have been used for the treatment of value of absolute log2 fold change >1 and corrected P<0.05. RCC; however, the effectiveness is limited (6). Therefore, the Among the 5 dysregulated lncRNAs, 2 of them were prog- identification of potential biomarkers and therapeutic targets nostic biomarkers according to the overall survival analysis for for RCC is urgently needed. patients with renal cell carcinoma. We successfully constructed With the advancement of techniques used in genome-wide a dysregulated lncRNA-associated ceRNA network, which platforms, long non-coding RNAs (lncRNAs) have been included 4 renal cell carcinoma-specific lncRNAs, 17 mRNAs identified and defined as RNA molecules of greater than 200 and 2 miRNAs. In summary, the present study identified nucleotides in length and without apparent protein-coding new lncRNA biomarkers and potential targets for renal cell potential (7,8). Thousands of lncRNAs in both humans carcinoma therapy. In particular, the novel ceRNA network and mice have been identified by the combined analysis of identified in our study will be vital for understanding the Chip-seq and RNA-seq data; however, only a few have been assigned any function (9-11). Accumulating evidence suggests that lncRNAs play a vital role in various biological responses, such as the regulation of epigenetic silencing by chromatin remodeling, regulation of splicing, recruitment of transcription factors, and regulation of mRNA stability. lncRNAs can func- Correspondence to: Professor Yuanjie Niu, Department of tion by regulating the alternative splicing of pre-mRNAs and Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin as competing endogenous RNAs (ceRNAs) that competitively Medical University, 23 Pingjiang Road, Hexi, Tianjin 300211, P.R. China bind to microRNAs (miRNAs) to suppress the inactivation of E-mail: [email protected] the target genes of miRNAs (12-14). Considering the potential significance of lncRNAs in physiological and pathological *Contributed equally responses, many efforts have been made to elucidate the func- tion of lncRNAs in carcinogenesis and cancer metastasis (15). Key words: renal cell carcinoma, lncRNA, ceRNA, miRNA, GEO miRNAs are another class of non-coding RNAs with a length of ~22 nucleotides that have been extensively studied (16). miRNAs regulate the expression of target genes 960 GAO et al: NETWORK ANALYSIS OF RENAL CELL CARCINOMA RNA EXPRESSION PROFILES by partial complementary binding to miRNA response the original data and screening of the differentially expressed elements (MREs), which contain the corresponding mRNA genes. The Benjamini-Hochberg (BH) method was used for sequences (17). One miRNA is able to regulate several mRNA statistical corrections. The online tool GEO2R was used for transcripts, and one transcript may be the target of several the extraction of differentially expressed genes as original data different miRNAs. The miRNA regulatory network plays of the expression level for GSE40911 and GSE71302 were not an important role in many biological responses, including available. In terms of the difference in expression threshold, carcinogenesis and tumor metastasis (18,19). ceRNAs are tran- genes were considered as significant with |log2FoldChange| >1 scripts that cross-regulate each other by competing for shared and corrected P<0.05. miRNAs (20,21). mRNAs, lncRNAs and other RNAs can After all genes with different expression levels were function as natural miRNA sponges by using shared MREs collected, which were determined according to the previously to suppress miRNA function (20). Certain lncRNAs have set threshold for GSE40911, the corresponding GPL3985 plat- been identified and experimentally validated (22). H19 is an form was downloaded to annotate the data. The empty lncRNA that modulates the let-7 miRNA family members and comment lines were deleted, and all the information of the miR-106a availability by acting as a molecular sponge (23,24). non-coding RNAs were filtered out. Based on the information The muscle-specific lncRNA linc-MD1 can interact with of the non-coding RNAs and all the differentially expressed miR-133 to regulate the expression of muscle-specific gene genes, DElncRNAs were obtained. expression (25). Such a RNA interaction could regulate many physiological and pathological responses and thus may Survival analysis. A total of 417 renal cancer samples in provide new ideas for cancer therapy. Thus far, the lncRNA- the database were retrieved from the Cancer Genome Atlas miRNA-mRNA ceRNA network in hepatocellular, breast and data portal. The survival package of R statistical program- gastric cancer, has been constructed and analyzed (26-29). ming software was used for the survival analysis of filtered However, similar studies involving RCC are rare. Moreover, DElncRNAs and DEmiRNAs. genome-wide comprehensive analysis of RCC-associated miRNAs and lncRNAs has been limited. Functional enrichment analysis. When a sufficient number of In the present study, we analyzed the mRNA, lncRNA, differentially expressed mRNAs (DEmRNAs) was obtained, and miRNA expression profiles from RCC-associated data- enrichment analysis of the differentially expressed genes was bases (GSE66270, GSE40914 and GSE71302, respectively). carried out using the cluster Profile package of R software. We identified a total of 2,378 aberrantly expressed RNAs; The enrichKEGG and enrichGO functions were used for 2 upregulated and 3 downregulated RNAs were categorized as KEGG and Gene Ontology (GO) enrichment analysis, respec- lncRNAs. Furthermore, we identified differentially expressed tively. GO terms and KEGG pathways with BH-corrected miRNAs (DEmiRNAs) in patients with RCC to elucidate the P<0.05 were filtered out to obtain the final results. As for the potential crosstalk between lncRNA, miRNA and mRNA. pathway that ranked first in KEGG enrichment analysis and Ultimately, a lncRNA-miRNA-mRNA ceRNA network was the pathway relevant to renal cancer, the Pathview package constructed from 4 dysregulated lncRNAs, 17 mRNAs and of R software was used for the mapping of related genes and 2 miRNAs by bioinformatic analysis. determination of the location of differentially expressed genes in the entire pathway. Materials and methods Construction of the ceRNA network and interactions among Study materials. Three RNA datasets (mRNA, lncRNA DEmRNAs. lncRNA-miRNA interactions and miRNA-mRNA and miRNA) were selected in this study. In these datasets, interactions were predicted using miRcode (http://www. GSE66270, GSE40914 and GSE71302 were analyzed as mircode.org/) and miRTarBase (http://mirtarbase.mbc.nctu. they were associated with renal cancer (30-32). GSE66270 edu.tw/) (33,34). The miRNA-mRNA pairs were validated (mRNA) of the Affymetrix Human Genome U133 Plus 2.0 by various methods including qRT-PCR, western blotting, Array (GPL570) platform consisted of 28 samples including ChIP-seq and microarray. To obtain a more reliable ceRNA 14 renal cancer and 14 normal samples. GSE40914 (lncRNA) network, high-correlation sets in the miRTarBase were was composed of three sub-datasets, GSE40911, GSE40912 selected to predict the interactions between miRNAs and and GSE40913. The GSE40911 dataset was selected for the mRNAs. The results of the lncRNA-miRNA-mRNA network extraction of differentially expressed lncRNAs (DElncRNAs).
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