An Integrated Analysis for Long Noncoding Rnas and Micrornas with the Mediated Competing Endogenous RNA Network in Papillary Renal Cell Carcinoma

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An Integrated Analysis for Long Noncoding Rnas and Micrornas with the Mediated Competing Endogenous RNA Network in Papillary Renal Cell Carcinoma Journal name: OncoTargets and Therapy Article Designation: Original Research Year: 2017 Volume: 10 OncoTargets and Therapy Dovepress Running head verso: Huang et al Running head recto: A ceRNA network in papillary renal cell carcinoma open access to scientific and medical research DOI: http://dx.doi.org/10.2147/OTT.S141951 Open Access Full Text Article ORIGINAL RESEARCH An integrated analysis for long noncoding RNAs and microRNAs with the mediated competing endogenous RNA network in papillary renal cell carcinoma Chuiguo Huang1,* Abstract: Papillary renal cell carcinoma (PRCC) is the second most common subtype of renal Naijun Yuan2,* cell carcinoma, and it lacks effective therapeutic targets and prognostic molecular biomarkers. Liying Wu3 Attention has been increasingly focused on long noncoding RNAs (lncRNAs), which can act Xiaofu Wang1 as competing endogenous RNA (ceRNA) to compete for shared microRNAs (miRNAs) in the Junqiang Dai4 tumorigenesis of human tumors. Therefore, to clarify the functional roles of lncRNAs with Pan Song5 respect to the mediated ceRNA network in PRCC, we comprehensively integrated expression profiles, including data on mRNAs, lncRNAs and miRNAs obtained from 289 PRCC tissues and Fengxi Li6 32 normal tissues in The Cancer Genome Atlas. As a result, we identified 2,197 differentially Changbao Xu1 expressed mRNAs (DEmRNAs) and 84 differentially expressed miRNAs (DEmiRNAs) using 1 Xinghua Zhao a threshold of |log2 (fold change)| .2.0 and an adjusted P-value ,0.05. To determine the hub 1Department of Urology, The Second DEmRNAs that could be key target genes, a weighted gene co-expression network analysis Affiliated Hospital of Zhengzhou was performed. A total of 28 hub DEmRNAs were identified as potential target genes. Seven University, Zhengzhou, 2College of Traditional Chinese Medicine dysregulated DEmiRNAs were identified that were significantly associated with the 28 hub of Jinan University, Institute of potential target genes. In addition, we found that 16 differentially expressed lncRNAs were able Integrated Traditional Chinese and Western Medicine of Jinan to interact with the DEmiRNAs. Finally, we used Cytoscape software to visualize the ceRNA University, Guangzhou, 3Department network with these differently expressed molecules. From these results, we believe that the of Nephrology, The Second identified ceRNA network plays a crucial role in the process of PRCC deterioration, and some Affiliated Hospital of Hainan Medical College, Hainan, 4Department of of the identified genes are strongly related to clinical prognosis. Neurosurgery, The Second Affiliated Keywords: papillary renal cell carcinoma, The Cancer Genome Atlas, weighted gene Hospital of Lanzhou University, co-expression network analysis, long noncoding RNA, competing endogenous RNA network, Lanzhou, 5Department of Urology, The First Affiliated Hospital of survival prognosis Zhengzhou University, Zhengzhou, 6Department of General Surgery, The First Affiliated Hospital of Guangxi Introduction Medical University, Guangxi, People’s Renal cell carcinoma (RCC) is a heterogeneous disease with varying histological Republic of China abnormalities, cytogenetic aberrations, responses to therapy, and prognoses and *These authors contributed equally 1 to this work accounts for 90% of renal malignancies in adults. The World Health Organization (WHO) stratified RCC into multiple distinct subtypes, including clear cell, papillary, Correspondence: Xinghua Zhao; Chuiguo Huang and chromophobe neoplasms. Papillary renal cell carcinoma (PRCC), the second most Department of Urology, The Second common subtype, accounts for about 10%–15% of RCC.2 Within standard therapeutic Affiliated Hospital of Zhengzhou protocols, malignant PRCC patients have a different pathological appearance and clinical University, Jingba Road, Zhengzhou 450014, Henan Province, People’s outcome. Current treatment strategies of PRCC include surgery, radiation therapy, and Republic of China chemotherapy, but a specialized, effective therapeutic remedy is still lacking.3 More- Email [email protected]; [email protected] over, relevant molecular targets for clinical therapy are deficient, and thus require submit your manuscript | www.dovepress.com OncoTargets and Therapy 2017:10 4037–4050 4037 Dovepress © 2017 Huang et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you http://dx.doi.org/10.2147/OTT.S141951 hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Huang et al Dovepress further validation by more comprehensive clinical trials uniporter, voltage-dependent anion channel 1 (VDAC1), with a larger number of samples. Furthermore, molecular and cytochrome C (CYC) have been identified as prognostic targets of drugs are subject to drug resistance and can cause biomarkers in the development of pancreatic ductal adenocar- toxicity leading to many restrictions in clinical application. cinoma eigengenes.11 Giulietti et al found that miR-302d-3p, Therefore, it is urgent and necessary that newly discovered miR-513c-5p, miR-3918, and miR-6076 could be candidate treatments are found, based on the specific mechanisms of miRNA biomarkers for pancreatic ductal adenocarcinoma PRCC carcinogenesis, to improve treatment efficiency and by targeting CYC.12 Tang et al showed that five novel avoid the adverse effects of conventional methods. lncRNAs (CYP4F26P, RP11-108M12.3, RP11-38M8.1, Advances in RNA sequencing technologies have brought RP11-54H7.4, and ZNF503-AS1), based on the prognostic to light the complexity of our genome. Noncoding RNAs signature, could be therapeutic targets for lung squamous cell (ncRNAs) account for the majority (98%) of the transcrip- carcinoma patients.13 Consequently, focusing on the coher- tome, and different classes of regulative RNA with impor- ence function of network modules is a powerful systematic tant biological functions are being continually discovered.4 analysis method.14 Investigating the world of RNA is one of the most important The Cancer Genome Atlas (TCGA) project has provided challenges facing biologists today, and long noncoding RNAs a comprehensive way to improve our ability to diagnose, (lncRNAs) represent potential new biomarkers and drug treat, and prevent tumor progression, through a better under- targets. Currently, a growing body of evidence has indicated standing of the genetic basis of cancer.15 By the end of 2015, that there are interactions between lncRNAs and microRNAs TCGA contained 33 types of cancer and .11,000 patients (miRNAs), the downstream target genes of which have been with gene expression profiles and relevant clinical data. Such closely related to tumor pathogenesis. In 2011, Salmena et al an enormous amount of data provides an ideal opportunity to presented a competing endogenous RNA (ceRNA) hypothesis, identify the mechanism and prognostic molecular signatures which described a complex posttranscriptional regulatory of cancer in a comprehensive way. Therefore, our research network, including lncRNAs, mRNAs, and other types of was based on TCGA, which analyzed the integrated RNA RNAs, which can act as natural miRNA sponges to suppress expression profiles from 289 PRCC samples and 32 normal miRNA functions by sharing one or more miRNA response samples. We also used the WGCNA to analyze the hub elements.5 Several experimental studies have also confirmed differentially expressed mRNAs (DEmRNAs), which can this hypothesis. For example, Cesana et al identified a muscle- be target genes. The databases, miRTarBase and miRcode, specific lncRNA, known as long intergenic non-protein-coding were used to screen the key differentially expressed lncRNAs RNA-muscle differentiation 1 (linc-MD1), which can mediate (DElncRNAs) and differentially expressed microRNAs the time of muscle differentiation by acting as a ceRNA in (DEmiRNAs), as well as DEmiRNAs–DEmRNAs inter- human myoblasts.6 Furthermore, Poliseno et al showed that actions. Hereafter, we constructed a ceRNA network to phosphatase and tensin homolog pseudogene 1 (PTENP1) elaborate the interactions and potential cross talk between the can upregulate the gene expression of PTEN by acting as a hub DElncRNAs, DEmiRNAs, and DEmRNAs. In addition, molecular sponge, causing adsorption of miR-19 and miR-20a relevant survival analyses were performed to determine the in prostate cancer, inhibiting tumor cell growth.7 However, to prognostic genes that possess clinical traits. date, there is still little research on ceRNA-related lncRNAs involved in relevant regulatory mechanisms in PRCC. Materials and methods Weighted gene co-expression network analysis (WGCNA) Study population has been widely used in determining changes in transcriptome We manually searched TCGA database, and a total of 289 expression patterns in various diseases, finding clusters that PRCC cases were enrolled for comprehensive integrated include highly correlated genes, and summarizing these analysis. In addition, we used the Data Transfer Tool clusters by the module eigengenes.8,9 Correlation networks (provided
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