scholarly journals Identification of hub genes and biological pathways in hepatocellular carcinoma by integrated bioinformatics analysis

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e10594
Author(s):  
Qian Zhao ◽  
Yan Zhang ◽  
Shichun Shao ◽  
Yeqing Sun ◽  
Zhengkui Lin

Background Hepatocellular carcinoma (HCC), the main type of liver cancer in human, is one of the most prevalent and deadly malignancies in the world. The present study aimed to identify hub genes and key biological pathways by integrated bioinformatics analysis. Methods A bioinformatics pipeline based on gene co-expression network (GCN) analysis was built to analyze the gene expression profile of HCC. Firstly, differentially expressed genes (DEGs) were identified and a GCN was constructed with Pearson correlation analysis. Then, the gene modules were identified with 3 different community detection algorithms, and the correlation analysis between gene modules and clinical indicators was performed. Moreover, we used the Search Tool for the Retrieval of Interacting Genes (STRING) database to construct a protein protein interaction (PPI) network of the key gene module, and we identified the hub genes using nine topology analysis algorithms based on this PPI network. Further, we used the Oncomine analysis, survival analysis, GEO data set and random forest algorithm to verify the important roles of hub genes in HCC. Lastly, we explored the methylation changes of hub genes using another GEO data (GSE73003). Results Firstly, among the expression profiles, 4,130 up-regulated genes and 471 down-regulated genes were identified. Next, the multi-level algorithm which had the highest modularity divided the GCN into nine gene modules. Also, a key gene module (m1) was identified. The biological processes of GO enrichment of m1 mainly included the processes of mitosis and meiosis and the functions of catalytic and exodeoxyribonuclease activity. Besides, these genes were enriched in the cell cycle and mitotic pathway. Furthermore, we identified 11 hub genes, MCM3, TRMT6, AURKA, CDC20, TOP2A, ECT2, TK1, MCM2, FEN1, NCAPD2 and KPNA2 which played key roles in HCC. The results of multiple verification methods indicated that the 11 hub genes had highly diagnostic efficiencies to distinguish tumors from normal tissues. Lastly, the methylation changes of gene CDC20, TOP2A, TK1, FEN1 in HCC samples had statistical significance (P-value < 0.05). Conclusion MCM3, TRMT6, AURKA, CDC20, TOP2A, ECT2, TK1, MCM2, FEN1, NCAPD2 and KPNA2 could be potential biomarkers or therapeutic targets for HCC. Meanwhile, the metabolic pathway, the cell cycle and mitotic pathway might played vital roles in the progression of HCC.

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e6645 ◽  
Author(s):  
Zhu Zhan ◽  
Yuhe Chen ◽  
Yuanqin Duan ◽  
Lin Li ◽  
Kenley Mew ◽  
...  

BackgroundLiver fibrosis is often a consequence of chronic liver injury, and has the potential to progress to cirrhosis and liver cancer. Despite being an important human disease, there are currently no approved anti-fibrotic drugs. In this study, we aim to identify the key genes and pathways governing the pathophysiological processes of liver fibrosis, and to screen therapeutic anti-fibrotic agents.MethodsExpression profiles were downloaded from the Gene Expression Omnibus (GEO), and differentially expressed genes (DEGs) were identified by R packages (Affy and limma). Gene functional enrichments of each dataset were performed on the DAVID database. Protein–protein interaction (PPI) network was constructed by STRING database and visualized in Cytoscape software. The hub genes were explored by the CytoHubba plugin app and validated in another GEO dataset and in a liver fibrosis cell model by quantitative real-time PCR assay. The Connectivity Map L1000 platform was used to identify potential anti-fibrotic agents.ResultsWe integrated three fibrosis datasets of different disease etiologies, incorporating a total of 70 severe (F3–F4) and 116 mild (F0–F1) fibrotic tissue samples. Gene functional enrichment analyses revealed that cell cycle was a pathway uniquely enriched in a dataset from those patients infected by hepatitis B virus (HBV), while the immune-inflammatory response was enriched in both the HBV and hepatitis C virus (HCV) datasets, but not in the nonalcoholic fatty liver disease (NAFLD) dataset. There was overlap between these three datasets; 185 total shared DEGs that were enriched for pathways associated with extracellular matrix constitution, platelet-derived growth-factor binding, protein digestion and absorption, focal adhesion, and PI3K-Akt signaling. In the PPI network, 25 hub genes were extracted and deemed to be essential genes for fibrogenesis, and the expression trends were consistent withGSE14323(an additional dataset) and liver fibrosis cell model, confirming the relevance of our findings. Among the 10 best matching anti-fibrotic agents, Zosuquidar and its corresponding gene target ABCB1 might be a novel anti-fibrotic agent or therapeutic target, but further work will be needed to verify its utility.ConclusionsThrough this bioinformatics analysis, we identified that cell cycle is a pathway uniquely enriched in HBV related dataset and immune-inflammatory response is clearly enriched in the virus-related datasets. Zosuquidar and ABCB1 might be a novel anti-fibrotic agent or target.


2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Ning Li ◽  
Ling Li ◽  
Yongshun Chen

Hepatocellular carcinoma (HCC) is one of the most common malignancies, which causes serious financial burden worldwide. This study aims to investigate the potential mechanisms contributing to HCC and identify core biomarkers. The HCC gene expression profile GSE41804 was picked out to analyze the differentially expressed genes (DEGs). Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were carried out using DAVID. We constructed a protein-protein interaction (PPI) network to visualize interactions of the DEGs. The survival analysis of these hub genes was conducted to evaluate their potential effects on HCC. In this analysis, 503 DEGs were captured (360 downregulated genes and 143 upregulated genes). Meanwhile, 15 hub genes were identified. GO analysis showed that the DEGs were mainly enriched in oxidative stress, cell cycle, and extracellular structure. KEGG analysis suggested the DEGs were enriched in the absorption, metabolism, and cell cycle pathway. PPI network disclosed that the top3 modules were mainly enriched in cell cycle, oxidative stress, and liver detoxification. In conclusion, our analysis uncovered that the alterations of oxidative stress and cell cycle are two major signatures of HCC. TOP2A, CCNB1, and KIF4A might promote the development of HCC, especially in proliferation and differentiation, which could be novel biomarkers and targets for diagnosis and treatment of HCC.


2019 ◽  
Vol 20 (5) ◽  
pp. 349-361
Author(s):  
Lu Zeng ◽  
Xiude Fan ◽  
Xiaoyun Wang ◽  
Huan Deng ◽  
Kun Zhang ◽  
...  

Background: Hepatocellular carcinoma (HCC) is the most common liver cancer and the mechanisms of hepatocarcinogenesis remain elusive. Objective: This study aims to mine hub genes associated with HCC using multiple databases. Methods: Data sets GSE45267, GSE60502, GSE74656 were downloaded from GEO database. Differentially expressed genes (DEGs) between HCC and control in each set were identified by limma software. The GO term and KEGG pathway enrichment of the DEGs aggregated in the datasets (aggregated DEGs) were analyzed using DAVID and KOBAS 3.0 databases. Protein-protein interaction (PPI) network of the aggregated DEGs was constructed using STRING database. GSEA software was used to verify the biological process. Association between hub genes and HCC prognosis was analyzed using patients’ information from TCGA database by survminer R package. Results: From GSE45267, GSE60502 and GSE74656, 7583, 2349, and 553 DEGs were identified respectively. A total of 221 aggregated DEGs, which were mainly enriched in 109 GO terms and 29 KEGG pathways, were identified. Cell cycle phase, mitotic cell cycle, cell division, nuclear division and mitosis were the most significant GO terms. Metabolic pathways, cell cycle, chemical carcinogenesis, retinol metabolism and fatty acid degradation were the main KEGG pathways. Nine hub genes (TOP2A, NDC80, CDK1, CCNB1, KIF11, BUB1, CCNB2, CCNA2 and TTK) were selected by PPI network and all of them were associated with prognosis of HCC patients. Conclusion: TOP2A, NDC80, CDK1, CCNB1, KIF11, BUB1, CCNB2, CCNA2 and TTK were hub genes in HCC, which may be potential biomarkers of HCC and targets of HCC therapy.


2021 ◽  
Vol 104 (3) ◽  
pp. 003685042110180
Author(s):  
Xiao Lin ◽  
Meng Zhou ◽  
Zehong Xu ◽  
Yusheng Chen ◽  
Fan Lin

In this study, we aimed to screen out genes associated with a high risk of postoperative recurrence of lung adenocarcinoma and investigate the possible mechanisms of the involvement of these genes in the recurrence of lung adenocarcinoma. We identify Hub genes and verify the expression levels and prognostic roles of these genes. Datasets of GSE40791, GSE31210, and GSE30219 were obtained from the Gene Expression Omnibus database. Enrichment analysis of gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were performed for the screened candidate genes using the DAVID database. Then, we performed protein–protein interaction (PPI) network analysis through the database STRING. Hub genes were screened out using Cytoscape software, and their expression levels were determined by the GEPIA database. Finally, we assessed the relationships of Hub genes expression levels and the time of survival. Forty-five candidate genes related to a high-risk of lung adenocarcinoma recurrence were screened out. Gene ontology analysis showed that these genes were enriched in the mitotic spindle assembly checkpoint, mitotic sister chromosome segregation, G2/M-phase transition of the mitotic cell cycle, and ATP binding, etc. KEGG analysis showed that these genes were involved predominantly in the cell cycle, p53 signaling pathway, and oocyte meiosis. We screened out the top ten Hub genes related to high expression of lung adenocarcinoma from the PPI network. The high expression levels of eight genes (TOP2A, HMMR, MELK, MAD2L1, BUB1B, BUB1, RRM2, and CCNA2) were related to short recurrence-free survival and they can be used as biomarkers for high risk of lung adenocarcinoma recurrence. This study screened out eight genes associated with a high risk of lung adenocarcinoma recurrence, which might provide novel insights into researching the recurrence mechanisms of lung adenocarcinoma as well as into the selection of targets in the treatment of the disease.


2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Weishuang Xue ◽  
Jinwei Li ◽  
Kailei Fu ◽  
Weiyu Teng

Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disease that affects the quality of life of elderly individuals, while the pathogenesis of AD is still unclear. Based on the bioinformatics analysis of differentially expressed genes (DEGs) in peripheral blood samples, we investigated genes related to mild cognitive impairment (MCI), AD, and late-stage AD that might be used for predicting the conversions. Methods. We obtained the DEGs in MCI, AD, and advanced AD patients from the Gene Expression Omnibus (GEO) database. A Venn diagram was used to identify the intersecting genes. Gene Ontology (GO) and Kyoto Gene and Genomic Encyclopedia (KEGG) were used to analyze the functions and pathways of the intersecting genes. Protein-protein interaction (PPI) networks were constructed to visualize the network of the proteins coded by the related genes. Hub genes were selected based on the PPI network. Results. Bioinformatics analysis indicated that there were 61 DEGs in both the MCI and AD groups and 27 the same DEGs among the three groups. Using GO and KEGG analyses, we found that these genes were related to the function of mitochondria and ribosome. Hub genes were determined by bioinformatics software based on the PPI network. Conclusions. Mitochondrial and ribosomal dysfunction in peripheral blood may be early signs in AD patients and related to the disease progression. The identified hub genes may provide the possibility for predicting AD progression or be the possible targets for treatments.


2022 ◽  
Vol 12 (3) ◽  
pp. 523-532
Author(s):  
Xin Yan ◽  
Chunfeng Liang ◽  
Xinghuan Liang ◽  
Li Li ◽  
Zhenxing Huang ◽  
...  

<sec> <title>Objective:</title> This study aimed to identify the potential key genes associated with the progression and prognosis of adrenocortical carcinoma (ACC). </sec> <sec> <title>Methods:</title> Differentially expressed genes (DEGs) in ACC cells and normal adrenocortical cells were assessed by microarray from the Gene Expression Omnibus database. The biological functions of the classified DEGs were examined by Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses and a protein–protein interaction (PPI) network was mapped using Cytoscape software. MCODE software was also used for the module analysis and then 4 algorithms of cytohubba software were used to screen hub genes. The overall survival (OS) examination of the hub genes was then performed by the ualcan online tool. </sec> <sec> <title>Results:</title> Two GSEs (GSE12368, GSE33371) were downloaded from GEO including 18 and 43 cases, respectively. One hundred and sixty-nine DEGs were identified, including 57 upregulated genes and 112 downregulated genes. The Gene Ontology (GO) analyses showed that the upregulated genes were significantly enriched in the mitotic cytokines is, nucleus and ATP binding, while the downregulated genes were involved in the positive regulation of cardiac muscle contraction, extracellular space, and heparin-binding (P < 0.05). The Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) pathway examination showed significant pathways including the cell cycle and the complement and coagulation cascades. The protein– protein interaction (PPI) network consisted of 162 nodes and 847 edges, including mitotic nuclear division, cytoplasmic, protein kinase binding, and cell cycle. All 4 identified hub genes (FOXM1, UBE2C, KIF11, and NDC80) were associated with the prognosis of adrenocortical carcinoma (ACC) by survival analysis. </sec> <sec> <title>Conclusions:</title> The present study offered insights into the molecular mechanism of adrenocortical carcinoma (ACC) that may be beneficial in further analyses. </sec>


PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11273
Author(s):  
Lei Yang ◽  
Weilong Yin ◽  
Xuechen Liu ◽  
Fangcun Li ◽  
Li Ma ◽  
...  

Background Hepatocellular carcinoma (HCC) is considered to be a malignant tumor with a high incidence and a high mortality. Accurate prognostic models are urgently needed. The present study was aimed at screening the critical genes for prognosis of HCC. Methods The GSE25097, GSE14520, GSE36376 and GSE76427 datasets were obtained from Gene Expression Omnibus (GEO). We used GEO2R to screen differentially expressed genes (DEGs). A protein-protein interaction network of the DEGs was constructed by Cytoscape in order to find hub genes by module analysis. The Metascape was performed to discover biological functions and pathway enrichment of DEGs. MCODE components were calculated to construct a module complex of DEGs. Then, gene set enrichment analysis (GSEA) was used for gene enrichment analysis. ONCOMINE was employed to assess the mRNA expression levels of key genes in HCC, and the survival analysis was conducted using the array from The Cancer Genome Atlas (TCGA) of HCC. Then, the LASSO Cox regression model was performed to establish and identify the prognostic gene signature. We validated the prognostic value of the gene signature in the TCGA cohort. Results We screened out 10 hub genes which were all up-regulated in HCC tissue. They mainly enrich in mitotic cell cycle process. The GSEA results showed that these data sets had good enrichment score and significance in the cell cycle pathway. Each candidate gene may be an indicator of prognostic factors in the development of HCC. However, hub genes expression was weekly associated with overall survival in HCC patients. LASSO Cox regression analysis validated a five-gene signature (including CDC20, CCNB2, NCAPG, ASPM and NUSAP1). These results suggest that five-gene signature model may provide clues for clinical prognostic biomarker of HCC.


2021 ◽  
Author(s):  
shenglan li ◽  
Zhuang Kang ◽  
jinyi Chen ◽  
Can Wang ◽  
Zehao Cai ◽  
...  

Abstract Background Medulloblastoma is a common intracranial tumor among children. In recent years, research on cancer genome has established four distinct subtypes of medulloblastoma: WNT, SHH, Group3, and Group4. Each subtype has its own transcriptional profile, methylation changes, and different clinical outcomes. Treatment and prognosis also vary depending on the subtype. Methods Based on the methylation data of medulloblastoma samples, methylCIBERSORT was used to evaluate the level of immune cell infiltration in medulloblastoma samples and identified 10 kinds of immune cells with different subtypes. Combined with the immune database, 293 Imm-DEGs were screened. Imm-DEGs were used to construct the co-expression network, and the key modules related to the level of differential immune cell infiltration were identified. Three immune hub genes (GAB1, ABL1, CXCR4) were identified according to the gene connectivity and the correlation with phenotype in the key modules, as well as the PPI network involved in the genes in the modules. Results The subtype marker was recognized according to the immune hub, and the subtype marker was verified in the external data set, the methylation level of immune hub gene among different subtypes was compared and analyzed, at the same time, tissue microarray was used for immunohistochemical verification, and a multi-factor regulatory network of hub gene was constructed. Conclusions Identifying subtype marker is helpful to accurately identify the subtypes of medulloblastoma patients, and can accurately evaluate the treatment and prognosis, so as to improve the overall survival of patients.


2019 ◽  
Vol 2019 ◽  
pp. 1-21 ◽  
Author(s):  
Meng Wang ◽  
Licheng Wang ◽  
Shusheng Wu ◽  
Dongsheng Zhou ◽  
Xianming Wang

Emerging evidence indicates that various functional genes with altered expression are involved in the tumor progression of human cancers. This study is aimed at identifying novel key genes that may be used for hepatocellular carcinoma (HCC) diagnosis, prognosis, and targeted therapy. This study included 3 expression profiles (GSE45267, GSE74656, and GSE84402), which were obtained from the Gene Expression Omnibus (GEO). GEO2R was used to analyze the differentially expressed genes (DEGs) between HCC and normal samples. The functional and pathway enrichment analysis was performed by the Database for Annotation, Visualization and Integrated Discovery. A protein-protein interaction (PPI) network of the identified DEGs was constructed using the Search Tool for the Retrieval of Interacting Gene, and hub genes were identified. ONCOMINE and CCLE databases were used to verify the expression of the hub genes in HCC tissues and cells. Kaplan-Meier plotter was used to assess the effects of the hub genes on the overall survival of HCC patients. A total of 99 DEGs were identified from the 3 expression profiles. These DEGs were enriched with functional processes and pathways related to HCC pathogenesis. From the PPI network, 5 hub genes were identified. The expression of the 5 hub genes was all upregulated in HCC tissues and cells compared with the control tissues and cells. Kaplan-Meier survival curves indicated that high expression of cyclin-dependent kinase (CDK1), cyclin B1 (CCNB1), cyclin B2 (CCNB2), MAD2 mitotic arrest deficient-like 1 (MAD2L1), and topoisomerase IIα (TOP2A) predicted poor overall survival in HCC patients (all log-rank P<0.01). These results revealed that the DEGs may serve as candidate key genes during HCC pathogenesis. The 5 hub genes, including CDK1, CCNB1, CCNB2, MAD2L1, and TOP2A, may serve as promising prognostic biomarkers in HCC.


2020 ◽  
Vol 25 (1) ◽  
Author(s):  
Xue Jiang ◽  
Zhijie Xu ◽  
Yuanyuan Du ◽  
Hongyu Chen

Abstract Background Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulopathy worldwide. However, the molecular events underlying IgAN remain to be fully elucidated. This study aimed to identify novel biomarkers of IgAN through bioinformatics analysis and elucidate the possible molecular mechanism. Methods Based on the microarray datasets GSE93798 and GSE37460 downloaded from the Gene Expression Omnibus database, the differentially expressed genes (DEGs) between IgAN samples and normal controls were identified. Using the DEGs, we further performed a series of functional enrichment analyses. Protein–protein interaction (PPI) networks of the DEGs were constructed using the STRING online search tool and were visualized using Cytoscape. Next, hub genes were identified and the most important module among the DEGs, Biological Networks Gene Ontology tool (BiNGO), was used to elucidate the molecular mechanism of IgAN. Results In total, 148 DEGs were identified, comprising 53 upregulated genes and 95 downregulated genes. Gene Ontology (GO) analysis indicated that the DEGs for IgAN were mainly enriched in extracellular exosome, region and space, fibroblast growth factor stimulus, inflammatory response, and innate immunity. Module analysis showed that genes in the top 1 significant module of the PPI network were mainly associated with innate immune response, integrin-mediated signaling pathway and inflammatory response. The top 10 hub genes were constructed in the PPI network, which could well distinguish the IgAN and control group in monocyte and tissue samples. We finally identified the integrin subunit beta 2 (ITGB2) and Fc fragment of IgE receptor Ig (FCER1G) genes that may play important roles in the development of IgAN. Conclusions We identified key genes along with the pathways that were most closely related to IgAN initiation and progression. Our results provide a more detailed molecular mechanism for the development of IgAN and novel candidate gene targets of IgAN.


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