Construction and comprehensive analysis of a ceRNA network to reveal potential prognostic biomarkers for hepatocellular carcinoma

Long, Junyu; Bai, Yi; Yang, Xiaobo; Lin, Jianzhen; Yang, Xu; Wang, Dongxu; He, Li; Zheng, Yongchang; Zhao, Hong

doi:10.1186/s12935-019-0817-y

Cited by 100 publications

(83 citation statements)

References 64 publications

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“…MiRNAs, included in ncRNAs, are identified to be evolutionarily conserved, with an average length of 22-nt, and may bind to the 3'untranslated region (3'UTR) of the targeted mRNAs according to the principle of complementary base pairing. An increasing body of evidence has demonstrated that dysregulated miRNAs play a crucial role in the initiation, progression, and therapy of various tumors [4,28,34]. Baolei et al revealed that miRNA-124 is a negative regulator of HCC with respect to proliferation and invasion by downregulating lncRNA-UCA1 [35].…”

Section: Discussionmentioning

confidence: 99%

“…Hepatocellular carcinoma (HCC) is one of the most universally malignant tumors in the world, with increasing morbidity and mortality [1,2]. Currently, it is the fifth most common cancer and the fourth leading cause of cancer-related death worldwide [3,4]. Tumorigenesis of HCC is correlated with several liver primary diseases, such as viral infections, including Hepatitis B virus (HBV), Hepatitis C virus (HCV), and other kinds of hepatotropic viruses, as well as alcoholic liver diseases, dietary aflatoxin exposure diabetes, and other diseases [5,6].…”

Section: Introductionmentioning

confidence: 99%

“…In 2011, the competing endogenous RNA (ceRNA) hypothesis was elucidated for the first time by Salmena et al, demonstrating that ncRNAs not only directly take part in the regulation of targeted gene expression but also absorb corresponding miRNAs as natural sponges due to their typically containing more than one miRNA response element (MRE) that competes with mRNA [9]. Recently, increasing evidence indicates that the regulatory network comprised of lncRNA-miRNA-mRNA plays an important role in the physiology and development of various tumors, including HCC, gallbladder cancer, gastric cancer, and others [3,4,7]. Zhang et al indicated that lncRNA-correlated ceRNA networks are involved in diverse biological cancer pathways in glioblastoma [10].…”

Section: Introductionmentioning

confidence: 99%

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Identification of Prognostic Biomarkers and Correlation with Immune Infiltrates in Hepatocellular Carcinoma Based on a Competing Endogenous RNA Network

Zhu

Wang

et al. 2020

Preprint

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Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Recently, competing endogenous RNAs (ceRNA) have revealed a significant role in the progression of HCC. Herein, we aimed to construct a ceRNA network to identify potential biomarkers and illustrate its correlation with immune infiltration in HCC. Methods: RNA sequencing data and clinical traits of HCC patients were downloaded from TCGA. The limma R package was used to identify differentially expressed (DE) RNAs. The predicted prognostic model was established using univariate and multivariate Cox regression. A K-M curve and GEPIA website were utilized for survival analysis. Functional annotation was determined using Enrichr and Reactome. Protein-to-protein network analysis was implemented using SRTNG and Cytoscape. Hub gene expression was validated by Oncomine and the Hunan Protein Atlas database. Immune infiltration was analyzed by TIMMER, and Drugbank was exploited to identify bioactive compounds. Results: The predicted model that was established revealed significant efficacy with 3- and 5-years of the area under ROC at 0.804 and 0.744, respectively. Eleven DEmiRNAs were screened out by a K-M survival analysis. Then, we constructed a ceRNA network, including 56 DElncRNAs, 6 DEmiRNAs, and 28 DEmRNAs. The 28 DEmRNAs were enriched in cancer-related pathways, for example, the TNF signaling pathway. Moreover, six hub genes, CEP55, DEPDC1, KIF23, CLSPN, MYBL2, and RACGAP1, were all overexpressed in HCC tissues and independently correlated with survival rate. Furthermore, expression of hub genes was related to immune cell infiltration in HCC, including B cells, CD8 + T cells, CD4 + T cells, monocytes, macrophages, neutrophils, and dendritic cells. Conclusions: The findings from this study demonstrate that CEP55, DEPDC1, KIF23, CLSPN, MYBL2, and RACGAP1 are closely associated with prognosis and immune infiltration, representing potential therapeutic targets or prognostic biomarkers in HCC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of Prognostic Biomarkers and Correlation with Immune Infiltrates in Hepatocellular Carcinoma Based on a Competing Endogenous RNA Network

Zhu

Wang

et al. 2020

Preprint

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“…By sponging microRNAs, lncRNAs revealed many significant instances of their influence on post-transcriptional regulation in a variety of cancers [41,42]. Their influence is controlled through mechanisms like the competitive endogenous model (ceRNA) [43] which will ultimately affect gene expression based on the binding activity of microRNAs. Despite established investigations of miRNA and lncRNA interactions, lncRNA-RBP binding activity is not well explored in a context of post-transcriptional regulation.…”

Section: Discussionmentioning

confidence: 99%

Long non-coding RNA expression levels modulate cell-type specific splicing patterns by altering their interaction landscape with RNA-binding proteins

Porto

Daulatabad

Janga

2019

Preprint

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Background: Recent developments in our understanding of the interactions between long non-coding RNAs (lncRNAs) and cellular components have improved treatment approaches for various human diseases including cancer, vascular diseases, and neurological diseases.Although investigation of specific lncRNAs revealed their role in the metabolism of cellular RNA, our understanding of their contribution to post-transcriptional regulation is relatively limited. In this study, we explore the role of lncRNAs in modulating alternative splicing and their impact on downstream protein-RNA interaction networks.Results: Analysis of alternative splicing events across 39 lncRNA knockdown and wildtype RNA-sequencing datasets from three human cell lines: HeLa (Cervical Cancer), K562 (Myeloid Leukemia), and U87 (Glioblastoma), resulted in high confidence (fdr < 0.01) identification of 11630 skipped exon events and 5895 retained intron events, implicating 759 genes to be impacted at post-transcriptional level due to the loss of lncRNAs. We observed that a majority of the alternatively spliced genes in a lncRNA knockdown were specific to the cell type, in tandem, the functions annotated to the genes affected by alternative splicing across each lncRNA knockdown also displayed cell type specificity. To understand the mechanism behind this cell-type specific alternative splicing patterns, we analyzed RNA binding protein (RBP)-RNA interaction profiles across the spliced regions, to observe cell type specific alternative splice event RBP binding preference.Conclusions: Despite limited RBP binding data across cell lines, alternatively spliced events detected in lncRNA perturbation experiments were associated with RBPs binding in proximal intron-exon junctions, in a cell type specific manner. The cellular functions affected by alternative splicing were also affected in a cell type specific manner. Based on the RBP binding profiles in HeLa and K562 cells, we hypothesize that several lncRNAs are likely to exhibit a sponge effect in disease contexts, resulting in the functional disruption of RBPs, and their downstream functions. We propose that such lncRNA sponges can extensively rewire the post-transcriptional gene regulatory networks by altering the protein-RNA interaction landscape in a cell-type specific manner. KeywordsLong non-coding RNA, cell type specific, alternative splicing, functional enrichment, RNAbinding proteins, protein binding lncRNA sponges, secondary RNA structure, and cancer.

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“…LncRNA NEAT1 contributes to lung cancer cell proliferation and invasion via NEAT1/miR-1224/KLF3 ceRNA pattern [10].Long intergenic non-coding RNA 00221 (LINC00221) was reported to enhance the cisplatin resistance of non-small cell lung cancer [11]. Also, LINC00221 is a prognostic biomarker for patients with hepatocellular carcinoma [12]. Besides, GEPIA database (http://gepia.cancer-pku.cn/) indicated that LINC00221 was conspicuously down-regulated in acute myeloid leukemia.…”

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confidence: 99%

LINC00221 suppresses the malignancy of children acute lymphoblastic leukemia

Huang

Ren³

et al. 2020

Bioscience Reports

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Correspondence: Man Huang (huangman770@163.com)As the most common malignant disease in childhood, children acute lymphoblastic leukemia (ALL) is a heterogeneous disease caused by the accumulated genetic alterations. Long non-coding RNAs (lncRNAs) are reported as critical regulators in diseases. GEPIA database indicated that long intergenic non-protein coding RNA 221 (LINC00221) was conspicuously down-regulated in acute myeloid leukemia. However, its expression pattern in ALL has not been revealed. This work was carried out to study the role of LINC00221 in ALL cells. Quantitative real-time PCR (qRT-PCR) quantified LINC00221 expression in ALL cells. The function of LINC00221 in ALL was determined by ki-67 immunofluorescence staining, EdU, TUNEL, JC-1, and caspase-3/8/9 activity assays. RNA pull down and Ago2-RNA immunoprecipitation (RIP) assays investigated the interaction between miR-152-3p and LINC00221 or ATPase sarcoplasmic/endoplasmic reticulum Ca2 + transporting 2 (ATP2A2). Our study revealed the low expression of LINC00221 in ALL cells. Subsequently, LINC00221 was verified to bind with miR-152-3p. Moreover, functional assays pointed out that LINC00221 overexpression posed anti-proliferation and pro-apoptosis effects in ALL cells, and these effects could be separately reversed by miR-152-3p up-regulation. Afterward, LINC00221 was revealed to regulate ATP2A2 expression via sponging miR-152-3p. Additionally, ATP2A2 was verified to involve in regulating LINC00221-mediated ALL cell proliferation and apoptosis. In conclusion, LINC00221 suppressed ALL cell proliferation and boosted ALL cell apoptosis via sponging miR-152-3p to up-regulate ATP2A2. regulate COL1A1 expression, thus enhancing proliferation and migration ability of breast cancer cells [7]. COL1A1-014 functions as a ceRNA in gastric cancer development via up-regulating CXCL12 and CXCR4 through interacting with miR-1273h-5p [8]. Up-regulation of lncRNA HOTAIR promotes PRAF2 expression via acting as a sponge of miR-326 in cutaneous squamous cell carcinoma [9]. LncRNA NEAT1 contributes to lung cancer cell proliferation and invasion via NEAT1/miR-1224/KLF3 ceRNA pattern [10].Long intergenic non-coding RNA 00221 (LINC00221) was reported to enhance the cisplatin resistance of non-small cell lung cancer [11]. Also, LINC00221 is a prognostic biomarker for patients with hepatocellular carcinoma [12]. Besides, GEPIA database (http://gepia.cancer-pku.cn/) indicated that LINC00221 was conspicuously down-regulated in acute myeloid leukemia. However, the expression pattern and functional role of LINC00221 in ALL are still uncovered. Thus, the study was designed to explore the function and underlying mechanism of LINC00221 in ALL cells. Materials and methods Cell cultureHuman ALL cell lines (Jurkat, CCRF-CEM, CEM/C1, 1301) and normal HEK 293T cell line were available from the ATCC (Manassas, VA) and cultivated in 5% CO 2 at 37 • C. Cell samples were all maintained in RPMI-1640 medium, with 10% FBS (HyClone, Logan, UT) and 1% penicillin-streptomycin as supplements. RNA...

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Construction and comprehensive analysis of a ceRNA network to reveal potential prognostic biomarkers for hepatocellular carcinoma

Cited by 100 publications

References 64 publications

Identification of Prognostic Biomarkers and Correlation with Immune Infiltrates in Hepatocellular Carcinoma Based on a Competing Endogenous RNA Network

Identification of Prognostic Biomarkers and Correlation with Immune Infiltrates in Hepatocellular Carcinoma Based on a Competing Endogenous RNA Network

Long non-coding RNA expression levels modulate cell-type specific splicing patterns by altering their interaction landscape with RNA-binding proteins

LINC00221 suppresses the malignancy of children acute lymphoblastic leukemia

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