scholarly journals Genome-Wide Analysis of Prognostic lncRNAs, miRNAs, and mRNAs Forming a Competing Endogenous RNA Network in Hepatocellular Carcinoma

2018 ◽  
Vol 48 (5) ◽  
pp. 1953-1967 ◽  
Author(s):  
Peng Lin ◽  
Dong-yue Wen ◽  
Qing Li ◽  
Yun He ◽  
Hong Yang ◽  
...  

Background/Aims: Hepatocellular carcinoma (HCC) is the most prevalent subtype of primary liver tumor worldwide. Growing evidence has led to a consensus that long non-coding RNAs (lncRNAs) have considerable influence on tumorigenesis and tumor progression of HCC via the mechanism of competing endogenous RNAs (ceRNAs). Methods: Here, we systematically investigated the expression landscape and clinical prognostic value of lncRNAs, micorRNAs (miRNAs), and mRNAs from The Cancer Genome Atlas. Differentially expressed RNAs were submitted to Cox regression analysis and the construction of prognostic indexes. A lncRNA-miRNA-mRNA regulatory network was then constructed based on interaction information derived from miRcode, TargetScan, miRTarBase, and miRDB. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to reveal and determine the functional roles of the ceRNA network in the prognosis of HCC. Results: We detected 77 differentially expressed lncRNAs, 29 differentially expressed miRNAs, and 1014 differentially expressed mRNAs in HCC, which were significantly associated with the overall survival of patients with HCC. We developed three prognostic prediction models that showed moderate predicting prognosis performance and were highly correlated with tumor burden, histological grade and pathological stage. Additionally, 10 survival-related lncRNAs, 6 survival-related miRNAs, and 31 survival-related mRNAs were included to develop a ceRNA network. Further functional enrichment analysis suggested that the ceRNA network was associated with a dismal prognosis for patients with HCC by disturbing the homeostasis of the cell cycle. Conclusion: Together, our study highlights the significant roles of lncRNAs in the development and implementation of monitoring surveillance and prognosis of HCC and provides a deeper understanding of the lncRNA-related ceRNA regulatory mechanism in the pathogenesis of HCC.


2020 ◽  
Author(s):  
Ze-bing Song ◽  
Guo-pei Zhang ◽  
shaoqiang li

Abstract Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumor in the world which prognosis is poor. Therefore, a precise biomarker is needed to guide treatment and improve prognosis. More and more studies have shown that lncRNAs and immune response are closely related to the prognosis of hepatocellular carcinoma. The aim of this study was to establish a prognostic signature based on immune related lncRNAs for HCC.Methods: Univariate cox regression analysis was performed to identify immune related lncRNAs, which had negative correlation with overall survival (OS) of 370 HCC patients from The Cancer Genome Atlas (TCGA). A prognostic signature based on OS related lncRNAs was identified by using multivariate cox regression analysis. Gene set enrichment analysis (GSEA) and a competing endogenous RNA (ceRNA) network were performed to clarify the potential mechanism of lncRNAs included in prognostic signature. Results: A prognostic signature based on OS related lncRNAs (AC145207.5, AL365203.2, AC009779.2, ZFPM2-AS1, PCAT6, LINC00942) showed moderately in prognosis prediction, and related with pathologic stage (Stage I&II VS Stage III&IV), distant metastasis status (M0 VS M1) and tumor stage (T1-2 VS T3-4). CeRNA network constructed 15 aixs among differentially expressed immune related genes, lncRNAs included in prognostic signature and differentially expressed miRNA. GSEA indicated that these lncRNAs were involved in cancer-related pathways. Conclusion: We constructed a prognostic signature based on immune related lncRNAs which can predict prognosis and guide therapies for HCC.



2020 ◽  
Author(s):  
Gaochen Lan ◽  
Xiaoling Yu ◽  
Yanna Zhao ◽  
Jinjian Lan ◽  
Wan Li ◽  
...  

Abstract Background: Breast cancer is the most common malignant disease among women. At present, more and more attention has been paid to long non-coding RNAs (lncRNAs) in the field of breast cancer research. We aimed to investigate the expression profiles of lncRNAs and construct a prognostic lncRNA for predicting the overall survival (OS) of breast cancer.Methods: The expression profiles of lncRNAs and clinical data with breast cancer were obtained from The Cancer Genome Atlas (TCGA). Differentially expressed lncRNAs were screened out by R package (limma). The survival probability was estimated by the Kaplan‑Meier Test. The Cox Regression Model was performed for univariate and multivariate analysis. The risk score (RS) was established on the basis of the lncRNAs’ expression level (exp) multiplied regression coefficient (β) from the multivariate cox regression analysis with the following formula: RS=exp a1 * β a1 + exp a2 * β a2 +……+ exp an * β an. Functional enrichment analysis was performed by Metascape.Results: A total of 3404 differentially expressed lncRNAs were identified. Among them, CYTOR, MIR4458HG and MAPT-AS1 were significantly associated with the survival of breast cancer. Finally, The RS could predict OS of breast cancer (RS=exp CYTOR * β CYTOR + exp MIR4458HG * β MIR4458HG + exp MAPT-AS1 * β MAPT-AS1). Moreover, it was confirmed that the three-lncRNA signature could be an independent prognostic biomarker for breast cancer (HR=3.040, P=0.000).Conclusions: This study established a three-lncRNA signature, which might be a novel prognostic biomarker for breast cancer.



2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Hao Guo ◽  
Jing Zhou ◽  
Yanjun Zhang ◽  
Zhi Wang ◽  
Likun Liu ◽  
...  

Background. Hypoxia closely relates to malignant progression and appears to be prognostic for outcome in hepatocellular carcinoma (HCC). Our research is aimed at mining the hypoxic-related genes (HRGs) and constructing a prognostic predictor (PP) model on clinical prognosis in HCC patients. Methods. RNA-sequencing data about HRGs and clinical data of patients with HCC were obtained from The Cancer Genome Atlas (TCGA) database portal. Differentially expressed HRGs between HCC and para-carcinoma tissue samples were obtained by applying the Wilcox analysis in R statistical software. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were used for gene functional enrichment analyses. Then, the patients who were asked to follow up for at least one month were enrolled in the following study. Cox proportional risk regression model was applied to obtain key HRGs which related to overall survival (OS) in HCC. PP was constructed and defined, and the accuracy of PP was validated by constructing the signature in a training set and validation set. Connectivity map (CMap) was used to find potential drugs, and gene set cancer analysis (GSCA) was also performed to explore the underlying molecular mechanisms. Results. Thirty-seven differentially expressed HRGs were obtained. It contained 28 upregulated and 9 downregulated genes. After the univariate Cox regression model analysis, we obtained 27 prognosis-related HRGs. Of these, 25 genes were risk factors for cancer, and 2 genes were protective factors. The PP was composed by 12 key genes (HDLBP, SAP30, PFKP, DPYSL4, SLC2A1, HMOX1, PGK1, ERO1A, LDHA, ENO2, SLC6A6, and TPI1). GSCA results showed the overall activity of these 12 key genes in 10 cancer-related pathways. Besides, CMap identified deferoxamine, crotamiton, talampicillin, and lycorine might have effects with HCC. Conclusions. This study firstly reported 12 prognostic HRGs and constructed the model of the PP. This comprehensive research of multiple databases helps us gain insight into the biological properties of HCC and provides deferoxamine, crotamiton, talampicillin, and lycorine as potential drugs to fight against HCC.



2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Chao Li ◽  
Wu Yao ◽  
Congcong Zhao ◽  
Guo Yang ◽  
Jingjing Wei ◽  
...  

Background. Esophageal cancer is one of the most deadly malignant tumors. Among the common malignant tumors in the world, esophageal cancer is ranked seventh, which has a high mortality rate. Long noncoding RNAs (lncRNAs) play an important role in the occurrence and development of various tumors. lncRNAs can competitively bind microRNAs (miRNAs) with mRNA, which can regulate the expression level of the encoded gene at the posttranscriptional level. This regulatory mechanism is called the competitive endogenous RNA (ceRNA) hypothesis, and ceRNA has important research value in tumor-related research. However, the regulation of lncRNAs is less studied in the study of esophageal cancer. Methods. The Cancer Genome Atlas (TCGA) database was used to download transcriptome profiling data of esophageal cancer. Gene expression quantification data contains 160 cancer samples and 11 normal samples. These data were used to identify differentially expressed lncRNAs and mRNAs. miRNA expression data includes 185 cancer samples and 13 normal samples. The differentially expressed RNAs were identified using the edgeR package in R software. Then, the miRcode database was used to predict miRNAs that bind to lncRNAs. MiRTarBase, miRDB, and TargetScan databases were used to predict the target genes of miRNAs. Cytoscape software was used to draw ceRNA network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using DAVID 6.8. Finally, multifactor cox regression was used to screen lncRNAs related to prognosis. Results. We have screened 1331 DElncRNAs, 3193 DEmRNAs, and 162 DEmiRNAs. Among them, the ceRNA network contains 111 lncRNAs, 11 miRNAs, and 63 DEmRNAs. Finally, we established a prediction model containing three lncRNAs through multifactor Cox regression analysis. Conclusions. Our research screened out three independent prognostic lncRNAs from the ceRNA network and constructed a risk assessment model. This is helpful to understand the regulatory role of lncRNAs in esophageal cancer.



2020 ◽  
Author(s):  
Xinhong Liu ◽  
Fang Tan ◽  
Xingyao Long ◽  
Ruokun Yi ◽  
Dingyi Yang ◽  
...  

Abstract Background RNA binding proteins (RBPs) play an important role in a variety of cancers. However, the role of RBPs in colorectal adenocarcinoma (COAD) has not been studied. Integrated analysis of RBPs will provide a better understanding of disease genesis and new insights into COAD treatment. Methods The gene expression data and corresponding clinical information for COAD were downloaded from The Cancer Genome Atlas (TCGA) database. Univariate Cox regression analysis was used to screen for RBPs associated with COAD recurrence, and multivariate Cox proportional hazards regression analyses were used to identify genes that were associated with COAD recurrence. A nomogram was constructed to predict the recurrence of COAD, and a receiver operating characteristic (ROC) curve analysis was performed to determine the accuracy of the prediction models. The Human Protein Atlas database was used in prediction models to confirm the expression of key genes in COAD patients. Result A total of 177 differentially expressed RBPs was obtained, comprising 123 upregulated and 54 downregulated. GO and KEGG enrichment analysis showed that the differentially expressed RBPs were mainly related to mRNA metabolism, RNA processing and translation regulation. Seven RBP genes (TDRD6, POP1, TDRD7, PPARGC1A, LIN28B, LRRFIP2 and PNLDC1) were identified as prognosis-associated genes and were used to construct the prognostic model. Conclusion We constructed a COAD prognostic model through bioinformatics analysis, which indicated that prognostic model RBPs have a potential role in the diagnosis and prognosis of COAD. Moreover, the nomogram can effectively predict the 1-year, 3-year, and 5-year survival rate for COAD patients.



2020 ◽  
Author(s):  
Zaoqu Liu ◽  
Dechao Jiao ◽  
Xueliang Zhou ◽  
Yuan Yao ◽  
Zhaonan Li ◽  
...  

Abstract Background: A growing amount of evidence has suggested immune-related genes (IRGs) play a key role in the development of hepatocellular carcinoma (HCC). However, there have been no investigations proposing a reliable prognostic signature in terms of tumor immunology. This study aimed to develop a robust signature based on IRGs in HCC.Methods: A total of 597 HCC patients were enrolled. The TCGA database was utilized for discovery, and the ICGC database was utilized for validation. Multiple algorithms (including univariate Cox, LASSO, and multivariate Cox regression) were performed to identify key prognostic IRGs and establish an immune-related risk signature. Bioinformatics analysis and R soft tools were utilized to annotate underlying biological functions. Results: A total of 1416 differentially expressed mRNAs (DEMs) were screened in the TCGA cohort, of which 90 were differentially expressed IRGs (DEIRGs). Using univariate Cox regression analysis, we identified 33 prognostically relevant DEIRGs. Using LASSO regression and multivariate Cox regression analysis, we extracted 8 optimal DEIRGs (APLN, CDK4, CXCL2, ESR1, IL1RN, PSMD2, SEMA3F, and SPP1) to construct a risk signature with the ability to distinguish cases as having a high or low risk of unfavorable prognosis in the TCGA cohort, and the signature was verified in the ICGC cohort. The signature was prognostically significant in all stratified cohorts and was deemed an independent prognostic factor for HCC. We also built a nomogram with good performance by combining the signature with clinicopathological factors to increase the accuracy of predicting HCC prognosis. By investigating the relationship of the risk score and 8 risk genes from our signature with clinical traits, we found that the aberrant expression of the immune-related risk genes is correlated with the development of HCC. Moreover, the high-risk group was higher than the low-risk group in terms of tumor mutation burden (TMB), immune cell infiltration, and the expression of immune checkpoints (PD-1, PD-L1, and CTLA-4), and functional enrichment analysis indicated the signature enriched an intensive immune phenotype.Conclusions: This study developed a robust immune-related risk signature and built a predictive nomogram that reliably predict overall survival in HCC, which may be helpful for clinical management and personalized immunotherapy decisions.



2020 ◽  
Vol 11 ◽  
Author(s):  
Jian-Rong Sun ◽  
Chen-Fan Kong ◽  
Kun-Min Xiao ◽  
Jia-Lu Yang ◽  
Xiang-Ke Qu ◽  
...  

Hepatocellular carcinoma (HCC) is one of the most common types of malignancy and is associated with high mortality. Prior research suggests that long non-coding RNAs (lncRNAs) play a crucial role in the development of HCC. Therefore, it is necessary to identify lncRNA-associated therapeutic biomarkers to improve the accuracy of HCC prognosis. Transcriptomic data of HCC obtained from The Cancer Genome Atlas (TCGA) database were used in the present study. Differentially expressed RNAs (DERNAs), including 74 lncRNAs, 16 miRNAs, and 35 mRNAs, were identified using bioinformatics analysis. The DERNAs were subsequently used to reconstruct a competing endogenous RNA (ceRNA) network. A lncRNA signature was revealed using Cox regression analysis, including LINC00200, MIR137HG, LINC00462, AP002478.1, and HTR2A-AS1. Kaplan-Meier plot demonstrated that the lncRNA signature is highly accurate in discriminating high- and low-risk patients (P < 0.05). The area under curve (AUC) value exceeded 0.7 in both training and validation cohort, suggesting a high prognostic potential of the signature. Furthermore, multivariate Cox regression analysis indicated that both the TNM stage and the lncRNA signature could serve as independent prognostic factors for HCC (P < 0.05). Then, a nomogram comprising the TNM stage and the lncRNA signature was determined to raise the accuracy in predicting the survival of HCC patients. In the present study, we have introduced a ceRNA network that could contribute to provide a new insight into the identification of potential regulation mechanisms for the development of HCC. The five-lncRNA signature could serve as a reliable biosignature for HCC prognosis, while the nomogram possesses strong potential in clinical applications.



BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yang Zhai ◽  
Bin Zhao ◽  
Yuzhen Wang ◽  
Lina Li ◽  
Jingjin Li ◽  
...  

Abstract Background Lung adenocarcinoma (LUAD) is the most common pathology subtype of lung cancer. In recent years, immunotherapy, targeted therapy and chemotherapeutics conferred a certain curative effects. However, the effect and prognosis of LUAD patients are different, and the efficacy of existing LUAD risk prediction models is unsatisfactory. Methods The Cancer Genome Atlas (TCGA) LUAD dataset was downloaded. The differentially expressed immune genes (DEIGs) were analyzed with edgeR and DESeq2. The prognostic DEIGs were identified by COX regression. Protein-protein interaction (PPI) network was inferred by STRING using prognostic DEIGs with p value< 0.05. The prognostic model based on DEIGs was established using Lasso regression. Immunohistochemistry was used to assess the expression of FERMT2, FKBP3, SMAD9, GATA2, and ITIH4 in 30 cases of LUAD tissues. Results In total,1654 DEIGs were identified, of which 436 genes were prognostic. Gene functional enrichment analysis indicated that the DEIGs were involved in inflammatory pathways. We constructed 4 models using DEIGs. Finally, model 4, which was constructed using the 436 DEIGs performed the best in prognostic predictions, the receiver operating characteristic curve (ROC) was 0.824 for 3 years, 0.838 for 5 years, 0.834 for 10 years. High levels of FERMT2, FKBP3 and low levels of SMAD9, GATA2, ITIH4 expression are related to the poor overall survival in LUAD (p < 0.05). The prognostic model based on DEIGs reflected infiltration by immune cells. Conclusions In our study, we built an optimal prognostic signature for LUAD using DEIGs and verified the expression of selected genes in LUAD. Our result suggests immune signature can be harnessed to obtain prognostic insights.



2021 ◽  
Author(s):  
ligong lu ◽  
Shaoqing Liu ◽  
Shengni Hua ◽  
Zhenlin Zhang ◽  
Meixiao Zhan ◽  
...  

Abstract Background Hepatocellular carcinoma (HCC) is the most common subtype of liver cancer, and the systematic exploration of its prognostic indicators is urgently needed. In this study, we obtained 12 IRGs for the construction of a risk score prediction model in HCC by bioinformatics analysis. Methods Differentially expressed genes were screened using the R software edgeR package. Functional enrichment analysis was performed through gene ontology analyses as well as the Kyoto Encyclopedia of Genes and Genomes pathway analysis. Single factor and multi-factor Cox analysis were employed for survival analysis. We used the Timer software to examine the correlation between risk score and tumor-infiltrating immune cells. Results We identified 3,215 up-regulated and 1,044 down-regulated genes in HCC tissues based on a cohort from The Cancer Genome Atlas (TCGA). Differentially expressed immune-related genes (IRGs) and survival-associated IRGs were further identified. We also integrated multivariate Cox regression analyses to obtain 12 IRGs for the construction of a risk score prediction model, whose performance was verified using the Kaplan-Meier survival and receiver operating characteristic curve analyses. Our findings suggest that the risk score was associated with clinical characteristics and the infiltration of immune cells in HCC patients. Conclusions We obtained a risk score prediction model of 12 IRGs in HCC by bioinformatics analysis and confirmed its performance.



2021 ◽  
Author(s):  
Yiran Cai ◽  
Jin Cui ◽  
Huiqun Wu

Abstract Background Given that long non-coding RNAs (lncRNAs) involved in the tumor initiation or progression of the endometrium and that competing endogenous RNA (ceRNA) plays an important role in increasingly more biological processes, lncRNA-mediated ceRNA is likely to function in the pathogenesis of uterine corpus endometrial carcinoma (UCEC). Our present study aimed to explore the potential molecular mechanisms for the prognosis of UCEC through an lncRNA-mediated ceRNA network. Methods The transcriptome profiles and corresponding clinical profiles of UCEC dataset were retrieved from CPTAC and TCGA databases respectively. Differentially expressed genes (DEGs) in UCEC samples were identified via “Edge R” package. Then, an integrated bioinformatics analysis including functional enrichment analysis, tumor infiltrating immune cell(TIIC) analysis, Kaplan-Meier curve, Cox regression analysis were conducted to analyze the prognostic biomarkers. Results In the CPTAC dataset of UCEC, a ceRNA network comprised of 36 miRNAs, 123 lncRNAs and 124 targeted mRNAs was established, and 8 of 123 prognostic-related DElncRNAs(Differentially Expressed long noncoding RNA) were identified. While in the TCGA dataset, a ceRNA network comprised of 38 miRNAs, 83 lncRNAs and 110 targeted mRNAs was established, and 2 of 83 prognostic-related DElncRNAs were identified. After filtered by risk grouping and Cox regression analysis, 10 prognostic-related lncRNAs including LINC00443, LINC00483, C2orf48, TRBV11-2, MEG-8 were identified. In addition, 33 survival-related DEmRNAs(Differentially Expressed messager RNA) in two ceRNA networks were further validated in the HPA database. Finally, six lncRNA/miRNA/mRNA axes were established to elucidate prognostic regulatory roles in UCEC. Conclusion Several prognostic lncRNAs are identified and prognostic model of lncRNA-mediated ceRNA network is constructed, which promotes the understanding of UCEC development mechanisms and potential therapeutic targets.



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