Identification of Key Genes and Evaluation of Their Prognosis Potential in Hepatocellular Carcinoma by Integrated Bioinformatics Analysis

Abstract Background Hepatocellular carcinoma (HCC) is a malignancy causing highly death rate in the world. Despite the development of treatment strategies for HCC, prognosis of this malignancy remains unsatisfactory. In this study, we aimed to identify the target genes associated with the prognosis of HCC patients. Methods Three expression profiles of HCC tissues were extracted from the Gene Expression Omnibus database to explore the differentially expressed genes (DEGs) using GEO2R method. Functional enrichment analysis was performed to reveal the biological characteristics of DEGs. Protein-protein interaction (PPI) network was constructed using Cytoscape software. The survival curve of identified DEGs were tested by Kaplan-Meier analysis. Results We identified 15 DEGs (CYP39A1, CYR61, FOS, FOXO1, GADD45B, ID1, IL1RAP, MT1M, PHLDA1, RND3, SDS, SOCS2, TAT, S100P, and SPINK1) in HCC tissues. Prognosis analysis showed that 4 DEGs (FOXO1,SPINK1༌SOCS2, and TAT) correlated with overall survival time of HCC patients, which might serve as therapeutic targets for HCC patients. Conclusions By integrated bioinformatics analysis, we proposed a novel way to reveal key genes that closely relate to HCC development.

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Identification of Tumorigenic and Prognostic Biomarkers in Colorectal Cancer Based on microRNA Expression Profiles

BioMed Research International ◽

10.1155/2020/7136049 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Yuntao Shi ◽

Yingying Zhuang ◽

Jialing Zhang ◽

Mengxue Chen ◽

Shangnong Wu

Keyword(s):

Target Genes ◽

Cox Regression ◽

Expression Profiles ◽

Survival Rates ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

Risk Groups ◽

Normal Mucosa ◽

Microrna Expression ◽

Functional Enrichment

Objective. Although noncoding RNAs, especially the microRNAs, have been found to play key roles in CRC development in intestinal tissue, the specific mechanism of these microRNAs has not been fully understood. Methods. GEO and TCGA database were used to explore the microRNA expression profiles of normal mucosa, adenoma, and carcinoma. And the differential expression genes were selected. Computationally, we built the SVM model and multivariable Cox regression model to evaluate the performance of tumorigenic microRNAs in discriminating the adenomas from normal tissues and risk prediction. Results. In this study, we identified 20 miRNA biomarkers dysregulated in the colon adenomas. The functional enrichment analysis showed that MAPK activity and MAPK cascade were highly enriched by these tumorigenic microRNAs. We also investigated the target genes of the tumorigenic microRNAs. Eleven genes, including PIGF, TPI1, KLF4, RARS, PCBP2, EIF5A, HK2, RAVER2, HMGN1, MAPK6, and NDUFA2, were identified to be frequently targeted by the tumorigenic microRNAs. The high AUC value and distinct overall survival rates between the two risk groups suggested that these tumorigenic microRNAs had the potential of diagnostic and prognostic value in CRC. Conclusions. The present study revealed possible mechanisms and pathways that may contribute to tumorigenesis of CRC, which could not only be used as CRC early detection biomarkers, but also be useful for tumorigenesis mechanism studies.

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miRNA Mediated Noise Making of 3′UTR Mutations in Cancer

Genes ◽

10.3390/genes9110545 ◽

2018 ◽

Vol 9 (11) ◽

pp. 545 ◽

Cited By ~ 5

Author(s):

Wei Wu ◽

Lingxiang Wu ◽

Mengyan Zhu ◽

Ziyu Wang ◽

Min Wu ◽

...

Keyword(s):

Somatic Mutations ◽

Target Genes ◽

Expression Profiles ◽

Tumor Development ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

Functional Enrichment ◽

Messenger Rnas ◽

Cellular Functions ◽

Mrna Binding

Somatic mutations in 3′-untranslated regions (3′UTR) do not alter amino acids and are considered to be silent in cancers. We found that such mutations can promote tumor progression by altering microRNA (miRNA) targeting efficiency and consequently affecting miRNA–mRNA interactions. We identified 67,159 somatic mutations located in the 3′UTRs of messenger RNAs (mRNAs) which can alter miRNA–mRNA interactions (functional somatic mutations, funcMutations), and 69.3% of these funcMutations (the degree of energy change > 12 kcal/mol) were identified to significantly promote loss of miRNA-mRNA binding. By integrating mRNA expression profiles of 21 cancer types, we found that the expression of target genes was positively correlated with the loss of absolute affinity level and negatively correlated with the gain of absolute affinity level. Functional enrichment analysis revealed that genes carrying funcMutations were significantly enriched in the MAPK and WNT signaling pathways, and analysis of regulatory modules identified eighteen miRNA modules involved with similar cellular functions. Our findings elucidate a complex relationship between miRNA, mRNA, and mutations, and suggest that 3′UTR mutations may play an important role in tumor development.

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Identification of Key Genes Associated With the Process of Hepatitis B Inflammation and Cancer Transformation by Integrated Bioinformatics Analysis

Frontiers in Genetics ◽

10.3389/fgene.2021.654517 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jingyuan Zhang ◽

Xinkui Liu ◽

Wei Zhou ◽

Shan Lu ◽

Chao Wu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Hepatitis B ◽

Differential Expression ◽

Chronic Inflammation ◽

Differential Expression Analysis ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

Functional Enrichment ◽

Gene Markers ◽

Key Genes

BackgroundHepatocellular carcinoma (HCC) has become the main cause of cancer death worldwide. More than half of hepatocellular carcinoma developed from hepatitis B virus infection (HBV). The purpose of this study is to find the key genes in the transformation process of liver inflammation and cancer and to inhibit the development of chronic inflammation and the transformation from disease to cancer.MethodsTwo groups of GEO data (including normal/HBV and HBV/HBV-HCC) were selected for differential expression analysis. The differential expression genes of HBV-HCC in TCGA were verified to coincide with the above genes to obtain overlapping genes. Then, functional enrichment analysis, modular analysis, and survival analysis were carried out on the key genes.ResultsWe identified nine central genes (CDK1, MAD2L1, CCNA2, PTTG1, NEK2) that may be closely related to the transformation of hepatitis B. The survival and prognosis gene markers composed of PTTG1, MAD2L1, RRM2, TPX2, CDK1, NEK2, DEPDC1, and ZWINT were constructed, which performed well in predicting the overall survival rate.ConclusionThe findings of this study have certain guiding significance for further research on the transformation of hepatitis B inflammatory cancer, inhibition of chronic inflammation, and molecular targeted therapy of cancer.

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Identification and characterization of Piwi-interacting RNAs in human placentas of preeclampsia

Scientific Reports ◽

10.1038/s41598-021-95307-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jie He ◽

Miaomiao Chen ◽

Jiacheng Xu ◽

Jie Fang ◽

Zheng Liu ◽

...

Keyword(s):

Expression Pattern ◽

Human Placenta ◽

Target Genes ◽

Expression Profiles ◽

Differential Expression Analysis ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

Functional Enrichment ◽

Small Rna Sequencing ◽

Common Disease

AbstractPreeclampsia is a common disease of pregnancy that poses a serious threat to the safety of pregnant women and the fetus; however, the etiology of preeclampsia is inconclusive. Piwi-interacting RNAs (piRNAs) are novel non-coding RNAs that are present at high levels in germ cells and are associated with spermatogenesis. Emerging evidence demonstrated that piRNA is expressed in a variety of human tissues and is closely associated with tumorigenesis. However, changes in the piRNA expression profile in the placenta have not been investigated. In this study, we used small RNA sequencing to evaluate the differences in piRNA expression profiles between preeclampsia and control patients and potential functions. Differential expression analysis found 41 up-regulated and 36 down-regulated piRNAs in preeclamptic samples. In addition, the functional enrichment analysis of piRNAs target genes indicated that they were related to the extracellular matrix (ECM) formation and tissue-specific. Finally, we examined the expression pattern of the PIWL family proteins in the placenta, and PIWL3 and PIWIL4 were the primary subtypes in the human placenta. In summary, this study first summarized the changes in the expression pattern of piRNA in preeclampsia and provided new clues for the regulatory role of piRNA in the human placenta.

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Immunogenomic Landscape Analysis of Prognostic Immune-Related Genes in Hepatocellular Carcinoma

Journal of Healthcare Engineering ◽

10.1155/2021/3761858 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Peng Qin ◽

Mengyu Zhang ◽

Xue Liu ◽

Ziming Dong

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Expression Profiles ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Functional Enrichment ◽

Differentially Expressed ◽

Receptor Interaction ◽

Immune Related Genes

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death. HBV infection is an important risk factor for the tumorigenesis of HCC, given that the inflammatory environment is closely related to morbidity and prognosis. Consequently, it is of urgent importance to explore the immunogenomic landscape to supplement the prognosis of HCC. The expression profiles of immune‐related genes (IRGs) were integrated with 377 HCC patients to generate differentially expressed IRGs based on the Cancer Genome Atlas (TCGA) dataset. These IRGs were evaluated and assessed in terms of their diagnostic and prognostic values. A total of 32 differentially expressed immune‐related genes resulted as significantly correlated with the overall survival of HCC patients. The Gene Ontology functional enrichment analysis revealed that these genes were actively involved in cytokine‐cytokine receptor interaction. A prognostic signature based on IRGs (HSPA4, PSME3, PSMD14, FABP6, ISG20L2, TRAF3, NDRG1, NRAS, CSPG5, and IL17D) stratified patients into high-risk versus low-risk groups in terms of overall survival and remained as an independent prognostic factor in multivariate analyses after adjusting for clinical and pathologic factors. Several IRGs (HSPA4, PSME3, PSMD14, FABP6, ISG20L2, TRAF3, NDRG1, NRAS, CSPG5, and IL17D) of clinical significance were screened in the present study, revealing that the proposed clinical-immune signature is a promising risk score for predicting the prognosis of HCC.

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Understanding the Modus Operandi of MicroRNA Regulatory Clusters

Cells ◽

10.3390/cells8091103 ◽

2019 ◽

Vol 8 (9) ◽

pp. 1103 ◽

Cited By ~ 3

Author(s):

Arthur C. Oliveira ◽

Luiz A. Bovolenta ◽

Lucas Alves ◽

Lucas Figueiredo ◽

Amanda O. Ribeiro ◽

...

Keyword(s):

Gene Expression ◽

Target Genes ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Target Prediction ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

Functional Enrichment ◽

Modus Operandi ◽

Wide Range

MicroRNAs (miRNAs) are non-coding RNAs that regulate a wide range of biological pathways by post-transcriptionally modulating gene expression levels. Given that even a single miRNA may simultaneously control several genes enrolled in multiple biological functions, one would expect that these tiny RNAs have the ability to properly sort among distinctive cellular processes to drive protein production. To test this hypothesis, we scrutinized previously published microarray datasets and clustered protein-coding gene expression profiles according to the intensity of fold-change levels caused by the exogenous transfection of 10 miRNAs (miR-1, miR-7, miR-9, miR-124, miR-128a, miR-132, miR-133a, miR-142, miR-148b, miR-181a) in a human cell line. Through an in silico functional enrichment analysis, we discovered non-randomic regulatory patterns, proper of each cluster identified. We demonstrated that miRNAs are capable of equivalently modulate the expression signatures of target genes in regulatory clusters according to the biological function they are assigned to. Moreover, target prediction analysis applied to ten vertebrate species, suggest that such miRNA regulatory modus operandi is evolutionarily conserved within vertebrates. Overall, we discovered a complex regulatory cluster-module strategy driven by miRNAs, which relies on the controlled intensity of the repression over distinct targets under specific biological contexts. Our discovery helps to clarify the mechanisms underlying the functional activity of miRNAs and makes it easier to take the fastest and most accurate path in the search for the functions of miRNAs in any distinct biological process of interest.

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Identify Key Genes by Weighted Gene Co-Expression Network Analysis for Lung Adenocarcinoma

Nano LIFE ◽

10.1142/s1793984419400026 ◽

2019 ◽

Vol 09 (01n02) ◽

pp. 1940002

Author(s):

Jichen Xu ◽

Xianchun Zong ◽

Qianshu Ren ◽

Hongyu Wang ◽

Lijuan Zhao ◽

...

Keyword(s):

Gene Expression ◽

Network Analysis ◽

Lung Adenocarcinoma ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

Functional Enrichment ◽

Oocyte Meiosis ◽

Key Genes

The aim of this paper is to identify key genes in lung adenocarcinoma (LUAD) through weighted gene co-expression network analysis (WGCNA), and to further understand the molecular mechanism of LUAD. 107 gene expression profiles were downloaded from GSE10072 in the GEO database. We performed rigorous processing of the initial gene expression profile data. Subsequently, we used WGCNA to identify disease-driven modules and enforced functional enrichment analysis. The key genes were defined as the most connected genes in the driver module and were validated using the GSE75037 and TCGA database. GSE10072 removed 41 unpaired lung samples and 4 outliers. By analyzing the 62 samples using WGCNA, we obtained 26 modules and identified the brown and magenta modules as the driving modules for the LUAD. We found that the “Cell cycle”, “Oocyte meiosis” and “Progesterone-mediated oocyte maturation” pathways may be related to the occurrence of LUAD. GSE75037 removed 8 outlier and obtained 2909 differentially expressed genes (DEGs), 26 genes (9 genes in the brown module, 17 genes in the magenta module) overlap with key genes in the driver module. The results of the survival analysis suggest that 19 genes were significantly correlated with the patient’s survival time, including KPNA2, FEN1, RRM2, TOP2A, CENPF, MCM4, BIRC5, MELK, MAD2L1, CCNB1, CCNA2, KIF11, CDKN3, NUSAP1, CEP55, AURKA, NEK2, KIF14 and CDCA8, which may be potential biomarkers or therapeutic targets for LUAD. In this study, we provide a theoretical basis for further understanding the biological mechanism of LUAD through bioinformatics analysis of LUAD.

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Bioinformatic Analysis of Key Genes Related to Tumor Microenvironment in Hepatocellular Carcinoma

10.21203/rs.3.rs-508119/v1 ◽

2021 ◽

Author(s):

Jingxu Zhang ◽

Hao Liu ◽

Keyi Zhao ◽

Zhiye Bao ◽

Zhishuo Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

Bioinformatic Analysis ◽

Functional Enrichment ◽

Expression Data ◽

Hub Genes ◽

Oncomine Database ◽

Key Genes ◽

Low Expression

Abstract Background: Tumor microenvironment (TME) plays important roles in the development of different types of cancer. However, the critical regulatory members of TME related to hepatocellular carcinoma (HCC) remain unclear. In this study, a bioinformatic analysis based on Cancer Genome Atlas (TCGA) and Estimation of STromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) datasets was conducted to predict the key genes affecting TME in HCC.Material and Methods: First, 340 patients and 20531 genes’ expression data with ESTIMATE scores were filtered and combined to identify differentially expressed genes. Next, protein-protein interaction (PPI) network and functional enrichment analysis were conducted to find hub genes. Then, log-rank test and functional enrichment analysis were conducted on the consensus genes and hub genes. Finally, Kaplan-Meier curves of the hub genes were drawn. As verification, those genes were searched on Oncomine database.Results: Among all differentially expressed genes, 916 genes were expressed in both the immune and stromal groups. The Gene Ontology (GO) terms they enriched were T cell activation, leukocyte migration, collagen-containing matrix, external side of plasma membrane, receptor ligand and activator activity. Cytokine-cytokine receptor interaction was the most significant Kyoto Encyclopedia of Genes and Genomes (KEGG) term. Furthermore, cd3e, cd3g, hla-dpa1, hla-dpb1, lck, and map4k1 hub genes were low expressed in 304 patients, participating in a variety of responses including immune response−activating cell surface receptor signaling, immune response−activating signal transduction, clathrin−coated vesicle membrane, immune receptor activity， peptide binding and amide binding pathways. Their low expression was also verified on Oncomine database.Conclusion: cd3e, cd3g, hla-dpa1, hla-dpb1, lck, and map4k1 participated in many aspects related to TME, and their low expression constructs a signature, may predict a poor 5 years’ survival in hepatocellular carcinoma.

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Exosomal circRNA in Digestive System Tumors: The Main Player or Coadjuvants?

Frontiers in Oncology ◽

10.3389/fonc.2021.614462 ◽

2021 ◽

Vol 11 ◽

Author(s):

Haoying Wang ◽

Xi Zeng ◽

Ya Zheng ◽

Yuping Wang ◽

Yongning Zhou

Keyword(s):

Colorectal Cancer ◽

Gastric Cancer ◽

Hepatocellular Carcinoma ◽

Digestive System ◽

Target Genes ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

Circular Rna ◽

The Cancer Genome Atlas ◽

Functional Enrichment

Exosomes are a type of extracellular microvesicles with a diameter of 40–160 nm. Circular RNA (circRNA) is a type of closed circular RNA molecule that is highly conserved in evolution. Exosomal circRNA plays a vital role in the proliferation, invasion, migration, and drug resistance of digestive system tumors. In this study, we used The Cancer Genome Atlas (TCGA) database, UALCAN, Python crawler, miRTargetLink Human, Database for Annotation, Visualization, and Integrated Discovery (DAVID), micBioinformatic online tool, and Cytoscape software (3.7.1). The results showed that circ-RanGAP1 in gastric cancer, circUHRF1 in hepatocellular carcinoma, and circFMN2 in colorectal cancer regulate the malignant behavior of tumors and affect the expression of their host gene through sponging miR-877-3p, miR-449c-5p, and miR-1182, respectively. Twenty exosomal circRNAs regulate 6,570 target genes through sponging 23 miRNAs. Firstly, 270 of those target genes are regulated by two or more miRNAs, which are highly correlated with 83 tumor-related pathways and six Kyoto Encyclopedia of Genes and Genomes pathways. Secondly, 1,146 target genes were significantly differentially expressed in corresponding digestive system tumors, and functional enrichment analysis revealed that 78 of those were involved in 20 cancer-related pathways. In short, the bioinformatics analysis showed that these exosomal circRNAs are stably expressed in body fluids, and regulate the occurrence and development of gastric cancer, hepatocellular carcinoma, colorectal cancer, and other digestive system tumors through sponging miRNAs. Exosomal circRNAs may be used as biomarkers for the diagnosis of disease and identification of effective therapeutic targets in the future, as well as improve the prognosis of patients with digestive system tumors.

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Prognostic value of aberrantly expressed methylation genes in human hepatocellular carcinoma

Bioscience Reports ◽

10.1042/bsr20192593 ◽

2020 ◽

Vol 40 (10) ◽

Author(s):

Limin Zhen ◽

Gang Ning ◽

Lina Wu ◽

Yongyuan Zheng ◽

Fangji Yang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Prognostic Value ◽

Expression Profiles ◽

Methylation Status ◽

Gene Expression Profiles ◽

Enrichment Analysis ◽

Functional Enrichment Analysis ◽

Functional Enrichment ◽

Reference Database ◽

Hub Genes

Abstract Objectives: To identify the prognostic value of aberrantly methylated differentially expressed genes (DEGs) in hepatocellular carcinoma (HCC) and to explore the underlying mechanisms of tumorigenesis. Methods: Gene expression profiles (GSE65372 and GSE37988) were analyzed using GEO2R to obtain aberrantly methylated DEGs. Functional enrichment analysis of screened genes was performed by the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Cytoscape software was used to analyze the PPI network and to select hub genes. Transcriptional and proteinic expression data of hub genes were obtained through UALCAN and the Human Protein Reference Database. Finally, we analyzed the prognostic value of hub genes with the Kaplan–Meier Plotter and MethSurv database. Results: In total, 24 up-hypomethylated oncogenes and 37 down-hypermethylated tumor suppressor genes (TSGs) were identified, and 8 hub genes, including 4 up-hypomethylated oncogenes (CDC5L, MERTK, RHOA and YBX1) and 4 down-hypermethylated TSGs (BCR, DFFA, SCUBE2 and TP63), were selected by PPI. Higher expression of methylated CDC5L-cg05671347, MERTK-cg08279316, RHOA-cg05657651 and YBX1-cg16306148, and lower expression of methylated BCR-cg25410636, DFFA-cg20696875, SCUBE2-cg19000089 and TP63-cg06520450, were associated with better overall survival (OS) in HCC patients. Multivariate analysis also showed they were independent prognostic factors for OS of HCC patients. Conclusions: In summary, different expression of methylated genes above mentioned were associated with better prognosis in HCC patients. Altering the methylation status of these genes may be a therapeutic target for HCC, but it should be further evaluated in clinical studies.

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