scholarly journals Identification of Prognostic Biomarkers of Potential Hub Genes in Urothelial Carcinoma and Function in Microenvironment

Author(s):  
Wei Chu ◽  
Bing Zhang ◽  
Haifeng Gong ◽  
Qianqian Zhao ◽  
Jun Chen ◽  
...  

Abstract Background: Urothelial carcinoma (UC) is the most common histological type of urinary system. In the past decades, despite the advances in UC diagnosis and therapy, there are still challenges to improve the overall survival (OS) of UC patients. PD-L1 inhibitor and PD-1 inhibitor have been approved for treating invasive UC, however, only about 20% of patients with metastatic UC show clinical benefits from immune checkpoint inhibitors. Therefor, bioinformatics tools were utilized to screen prognostic-related biomarkers, and analyze their relationship with immunocyte in UC, hoping to provide new ideas for the clinical treatment of UC patients.Methods: Three gene expression profiles (i.e. GSE32548, GSE32894 and GSE48075) were selected from GEO, and divide them into invasive and superficial UC group for study. NetworkAnalyst tool was used to construct gene regulatory network of DEGs, while DAVID and Metascape were utilized to perform GO/KEGG enrichment analysis of DEGs. The hub genes were screened by STRING and cytoscape, and the ONCOMINE, GEPIA, UALCAN, cBioPortal and HPA databases were used to analyze the expression differences at the DNA, RNA, protein levels and prognostic of UC. TIMER was used to analyze the relationship between hub genes and immunocyte infiltration.Results: In total, 63 DEGs were identified from the GEO database of UC, of which 31 and 32 were up-and down-regulated. GO/KEGG pathway analysis identified DEGs were mainly enriched in the collagen catabolic process, extracellular matrix (ECM) organization, ECM structural constituent and ECM-receptor interaction. Nine hub genes (i.e. COL1A1, COL1A2, COL3A1, COL5A2, MMP9, POSTN, SPP1, VCAN and THBS2) upregulated in invasive UC compared with superficial UC were identified. cBioportal database analysis showed that 35% of UC patients presented genetic variants in the hub genes, of which amplification and deletion mutations were the most common. ONCOMINE and UALCAN database analysis showed that the mRNA expression of all hub genes in invasive UC was significantly higher than that in superficial UC and normal tissues. HPA database analysis showed that there was up-regulation of COL3A1, SPP1, POSTN and VCAN protein in UC tissues than in normal tissues. GEPIA showed that COL1A2, COL3A1, THBS2, and VCAN were positively correlated with the OS rate among patients with UC (P < 0.05). UALCAN showed that UC patients with high expression of COL1A1, COL1A2, COL5A2 and POSTN had a poorer prognosis (P < 0.05). TRRUST database analysis indicated that there was a significant correlation between the expression of the hub genes and the infiltration of CD4+T cells, CD8+T cells, macrophages, neutrophils and dendritic cells. Conclusion: Hub genes played important roles in pathogenesis and treatment prognosis of UC and they can provides new biomolecular predictions for immunotherapy and prognosis judgment of UC.

2021 ◽  
Author(s):  
Wei Chu ◽  
Bing Zhang ◽  
Haifeng Gong ◽  
Qianqian Zhao ◽  
Jun Chen ◽  
...  

Abstract Background Urothelial carcinoma (UC) is the most common histological type of urinary system. In the past decades, despite the advances in UC diagnosis and therapy, there are still challenges to improve the overall survival (OS) of UC patients. PD-L1 inhibitor and PD-1 inhibitor have been approved for treating invasive UC, however, only about 20% of patients with metastatic UC show clinical benefits from immune checkpoint inhibitors. Therefor, bioinformatics tools were utilized to screen prognostic-related biomarkers, and analyze their relationship with immunocyte in UC, hoping to provide new ideas for the clinical treatment of UC patients.Methods Three gene expression profiles (i.e. GSE32548, GSE32894 and GSE48075) were selected from GEO, and divide them into invasive and superficial UC group for study. NetworkAnalyst tool was used to construct gene regulatory network of DEGs, while DAVID and Metascape were utilized to perform gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis of DEGs. The hub genes were screened by STRING and cytoscape, and the ONCOMINE, GEPIA, UALCAN, cBioPortal and HPA databases were used to analyze the expression differences and survival curves of UC at the DNA, RNA, protein levels and protein levels. TIMER was used to analyze the relationship between hub genes and immunocyte infiltration.Results In total, 63 DEGs were identified from the GEO database of UC, of which 31 and 32 were up-and down-regulated. GO/KEGG pathway analysis identified DEGs were mainly enriched in the collagen catabolic process, extracellular matrix (ECM) organization, ECM structural constituent and ECM-receptor interaction. Nine hub genes (i.e. COL1A1, COL1A2, COL3A1, COL5A2, MMP9, POSTN, SPP1, VCAN and THBS2) upregulated in invasive UC compared with superficial UC were identified. cBioportal database analysis showed that 35% of UC patients presented genetic variants in the hub genes, of which amplification and deletion mutations were the most common. ONCOMINE and UALCAN database analysis showed that the mRNA expression of all hub genes in invasive UC was significantly higher than that in superficial UC and normal tissues. HPA database analysis showed that there was up-regulation of COL3A1, SPP1, POSTN and VCAN protein in UC tissues than in normal tissues. GEPIA showed that COL1A2, COL3A1, THBS2, and VCAN were positively correlated with the OS rate among patients with UC (P < 0.05). UALCAN showed that UC patients with high expression of COL1A1, COL1A2, COL5A2 and POSTN had a poorer prognosis (P < 0.05). TRRUST database analysis indicated that there was a significant correlation between the expression of the hub genes and the infiltration of CD4 + T cells, CD8 + T cells, macrophages, neutrophils and dendritic cells.Conclusion Hub genes played important roles in pathogenesis and treatment prognosis of UC. Hub genes analysis provides new predictive biomolecules for UC immunotherapy and prognosis judgment.


2021 ◽  
Author(s):  
Wei Chu ◽  
Bing Zhang ◽  
Haifeng Gong ◽  
Qianqian Zhao ◽  
Jun Chen ◽  
...  

Abstract Background: Urothelial carcinoma (UC) is the most common histological type of urinary system. In the past decades, despite the advances in UC diagnosis and therapy, there are still challenges to improve the overall survival (OS) of UC patients. PD-L1 inhibitor and PD-1 inhibitor have been approved for treating invasive UC, however, only about 20% of patients with metastatic UC show clinical benefits from immune checkpoint inhibitors. Therefor, bioinformatics tools were utilized to screen prognostic-related biomarkers, and analyze their relationship with immunocyte in UC, hoping to provide new ideas for the clinical treatment of UC patients.Results: In total, 63 DEGs were identified from the GEO database of UC, of which 31 and 32 were up-and down-regulated. GO/KEGG pathway analysis identified DEGs were mainly enriched in the collagen catabolic process, extracellular matrix (ECM) organization, ECM structural constituent and ECM-receptor interaction. Nine hub genes (i.e. COL1A1, COL1A2, COL3A1, COL5A2, MMP9, POSTN, SPP1, VCAN and THBS2) upregulated in invasive UC compared with superficial UC were identified. cBioportal database analysis showed that 35% of UC patients presented genetic variants in the hub genes, of which amplification and deletion mutations were the most common. ONCOMINE and UALCAN database analysis showed that the mRNA expression of all hub genes in invasive UC was significantly higher than that in superficial UC and normal tissues. HPA database analysis showed that there was up-regulation of COL3A1, SPP1, POSTN and VCAN protein in UC tissues than in normal tissues. GEPIA showed that COL1A2, COL3A1, THBS2, and VCAN were positively correlated with the OS rate among patients with UC (P < 0.05). UALCAN showed that UC patients with high expression of COL1A1, COL1A2, COL5A2 and POSTN had a poorer prognosis (P < 0.05). TRRUST database analysis indicated that there was a significant correlation between the expression of the hub genes and the infiltration of CD4+T cells, CD8+T cells, macrophages, neutrophils and dendritic cells. Conclusion: Hub genes played important roles in pathogenesis and treatment prognosis of UC and they can provides new biomolecular predictions for immunotherapy and prognosis judgment of UC.


2021 ◽  
Vol 24 (5-6) ◽  
pp. 267-279
Author(s):  
Xianyang Zhu ◽  
Wen Guo

<b><i>Background:</i></b> This study aimed to screen and validate the crucial genes involved in osteoarthritis (OA) and explore its potential molecular mechanisms. <b><i>Methods:</i></b> Four expression profile datasets related to OA were downloaded from the Gene Expression Omnibus (GEO). The differentially expressed genes (DEGs) from 4 microarray patterns were identified by the meta-analysis method. The weighted gene co-expression network analysis (WGCNA) method was used to investigate stable modules most related to OA. In addition, a protein-protein interaction (PPI) network was built to explore hub genes in OA. Moreover, OA-related genes and pathways were retrieved from Comparative Toxicogenomics Database (CTD). <b><i>Results:</i></b> A total of 1,136 DEGs were identified from 4 datasets. Based on these DEGs, WGCNA further explored 370 genes included in the 3 OA-related stable modules. A total of 10 hub genes were identified in the PPI network, including <i>AKT1</i>, <i>CDC42</i>, <i>HLA-DQA2</i>, <i>TUBB</i>, <i>TWISTNB</i>, <i>GSK3B</i>, <i>FZD2</i>, <i>KLC1</i>, <i>GUSB</i>, and <i>RHOG</i>. Besides, 5 pathways including “Lysosome,” “Pathways in cancer,” “Wnt signaling pathway,” “ECM-receptor interaction” and “Focal adhesion” in CTD and enrichment analysis and 5 OA-related hub genes (including <i>GSK3B, CDC42, AKT1, FZD2</i>, and <i>GUSB</i>) were identified. <b><i>Conclusion:</i></b> In this study, the meta-analysis was used to screen the central genes associated with OA in a variety of gene expression profiles. Three OA-related modules (green, turquoise, and yellow) containing 370 genes were identified through WGCNA. It was discovered through the gene-pathway network that <i>GSK3B, CDC42, AKT1, FZD2</i>, <i>and GUSB</i> may be key genes related to the progress of OA and may become promising therapeutic targets.


2021 ◽  
Author(s):  
Weina Lu ◽  
Ran Ji

Abstract Background and Aims: Acute respiratory distress syndrome (ARDS) is one of the most common acute thoracopathy with complicated pathogenesis in ICU. The study is to explore the differentially expressed genes (DEGs) in the lung tissue and underlying altering mechanisms in ARDS.Methods: Gene expression profiles of GSE2411 and GSE130936 were available from GEO database, both of them included in GPL 339. Then, an integrated analysis of these genes was performed, including gene ontology (GO) and KEGG pathway enrichment analysis, protein-protein interaction (PPI) network construction, Transcription Factors (TFs) forecasting, and their expression in varied organs.Results: A total of 39 differential expressed genes were screened from the datasets, including 39 up-regulated genes and 0 down-regulated genes. The up-regulated genes were mainly enriched in the biological process, such as immune system process, innate immune response, inflammatory response, cellular response to interferon-beta and also involved in some signal pathways, including cytokine-cytokine receptor interaction, salmonella infection, legionellosis, chemokine, and Toll-like receptor signal pathway. GBP2, IFIT2 and IFIT3 were identified as hub genes in the lung by PPI network analysis with MCODE plug-in, as well as GO and KEGG re-enrichment. All of the three hub genes were regulated by the predictive common TFs, including STAT1, E2F1, IRF1, IRF2, and IRF9. Conclusions: This study implied that hub gene GBP2, IFIT2 and IFIT3, which might be regulated by STAT1, E2F1, IRF1, IRF2, or IRF9, played significant roles in ARDS. They could be potential diagnostic or therapeutic targets for ARDS patients.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Weina Lu ◽  
Ran Ji

Abstract Background and aims Acute respiratory distress syndrome (ARDS) or acute lung injury (ALI) is one of the most common acute thoracopathy with complicated pathogenesis in ICU. The study is to explore the differentially expressed genes (DEGs) in the lung tissue and underlying altering mechanisms in ARDS. Methods Gene expression profiles of GSE2411 and GSE130936 were available from GEO database, both of them included in GPL339. Then, an integrated analysis of these genes was performed, including gene ontology (GO) and KEGG pathway enrichment analysis in DAVID database, protein–protein interaction (PPI) network construction evaluated by the online database STRING, Transcription Factors (TFs) forecasting based on the Cytoscape plugin iRegulon, and their expression in varied organs in The Human Protein Atlas. Results A total of 39 differential expressed genes were screened from the two datasets, including 39 up-regulated genes and 0 down-regulated genes. The up-regulated genes were mainly enriched in the biological process, such as immune system process, innate immune response, inflammatory response, and also involved in some signal pathways, including cytokine–cytokine receptor interaction, Salmonella infection, Legionellosis, Chemokine, and Toll-like receptor signal pathway with an integrated analysis. GBP2, IFIT2 and IFIT3 were identified as hub genes in the lung by PPI network analysis with MCODE plug-in, as well as GO and KEGG re-enrichment. All of the three hub genes were regulated by the predictive common TFs, including STAT1, E2F1, IRF1, IRF2, and IRF9. Conclusions This study implied that hub gene GBP2, IFIT2 and IFIT3, which might be regulated by STAT1, E2F1, IRF1, IRF2, or IRF9, played significant roles in ARDS. They could be potential diagnostic or therapeutic targets for ARDS patients.


BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Baojie Wu ◽  
Shuyi Xi

Abstract Background This study aimed to explore and identify key genes and signaling pathways that contribute to the progression of cervical cancer to improve prognosis. Methods Three gene expression profiles (GSE63514, GSE64217 and GSE138080) were screened and downloaded from the Gene Expression Omnibus database (GEO). Differentially expressed genes (DEGs) were screened using the GEO2R and Venn diagram tools. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Gene set enrichment analysis (GSEA) was performed to analyze the three gene expression profiles. Moreover, a protein–protein interaction (PPI) network of the DEGs was constructed, and functional enrichment analysis was performed. On this basis, hub genes from critical PPI subnetworks were explored with Cytoscape software. The expression of these genes in tumors was verified, and survival analysis of potential prognostic genes from critical subnetworks was conducted. Functional annotation, multiple gene comparison and dimensionality reduction in candidate genes indicated the clinical significance of potential targets. Results A total of 476 DEGs were screened: 253 upregulated genes and 223 downregulated genes. DEGs were enriched in 22 biological processes, 16 cellular components and 9 molecular functions in precancerous lesions and cervical cancer. DEGs were mainly enriched in 10 KEGG pathways. Through intersection analysis and data mining, 3 key KEGG pathways and related core genes were revealed by GSEA. Moreover, a PPI network of 476 DEGs was constructed, hub genes from 12 critical subnetworks were explored, and a total of 14 potential molecular targets were obtained. Conclusions These findings promote the understanding of the molecular mechanism of and clinically related molecular targets for cervical cancer.


2021 ◽  
Author(s):  
Sheng Fang ◽  
Xiao Fang ◽  
Xin Xu ◽  
Lin Zhong ◽  
An-quan Wang ◽  
...  

Abstract Relevance Rheumatoid arthritis (RA) is a systemic autoimmune disease with an aggressive, chronic synovial inflammation as the main pathological change. However, the specific etiology, pathogenesis, and related biomarkers in diagnosis and treatment are still not fully elucidated. This study attempts to provide new perspectives and insights into RA at the genetic, molecular, and cellular levels through the tenet of personalized medicine. Methods Gene expression profiles of four individual knee synovial tissues were downloaded from a comprehensive gene expression database, R language was used to screen for significantly differentially expressed genes (DEGs), Gene Ontology Enrichment Analysis, Kyoto Gene Encyclopedia, and Gene Set Enrichment Analysis were performed to analyze the biological functions and signaling pathways of these DEGs, STRING online database was used to establish protein-protein interaction networks, Cytoscape software to obtain ten hub genes, Goplot to get six inflammatory immune-related hub genes, and CIBERSORT algorithm to impute immune infiltration. Results Molecular pathways that play important roles in RA were obtained: Toll-like receptors, AMPK, MAPK, TNF, FoxO, TGF-beta, PI3K and NF-κB pathways, Ten hub genes: Ccr1, Ccr2, Ccr5, Ccr7, Cxcl5, Cxcl6, Cxcl13, Ccl13, Adcy2, and Pnoc. among which Adcy2 and Pnoc have not been reported in RA studies, suggesting that they may be worthy targets for further study. It was also found that among the synoviocytes in RA, the proportions of plasma cells, CD8 T cells, follicular helper T cells, monocytes, γ delta T cells, and M0 macrophages were higher, while the proportions of CD4 memory resting T cells, regulatory T cells (Tregs), activated NK cells, resting dendritic cells, M1 macrophages, eosinophils, activated mast cells, resting mast cells were lower in proportion, and each cell played an important role in RA. Conclusions This study may help understand the key genes, molecular pathways, the role of inflammatory immune infiltrating cells in RA’s pathogenesis and provide new targets and ideas for the diagnosis and personalized treatment of RA.


2022 ◽  
Vol 2022 ◽  
pp. 1-17
Author(s):  
Md. Rakibul Islam ◽  
Lway Faisal Abdulrazak ◽  
Mohammad Khursheed Alam ◽  
Bikash Kumar Paul ◽  
Kawsar Ahmed ◽  
...  

Background. Medulloblastoma (MB) is the most occurring brain cancer that mostly happens in childhood age. This cancer starts in the cerebellum part of the brain. This study is designed to screen novel and significant biomarkers, which may perform as potential prognostic biomarkers and therapeutic targets in MB. Methods. A total of 103 MB-related samples from three gene expression profiles of GSE22139, GSE37418, and GSE86574 were downloaded from the Gene Expression Omnibus (GEO). Applying the limma package, all three datasets were analyzed, and 1065 mutual DEGs were identified including 408 overexpressed and 657 underexpressed with the minimum cut-off criteria of ∣ log   fold   change ∣ > 1 and P < 0.05 . The Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and WikiPathways enrichment analyses were executed to discover the internal functions of the mutual DEGs. The outcomes of enrichment analysis showed that the common DEGs were significantly connected with MB progression and development. The Search Tool for Retrieval of Interacting Genes (STRING) database was used to construct the interaction network, and the network was displayed using the Cytoscape tool and applying connectivity and stress value methods of cytoHubba plugin 35 hub genes were identified from the whole network. Results. Four key clusters were identified using the PEWCC 1.0 method. Additionally, the survival analysis of hub genes was brought out based on clinical information of 612 MB patients. This bioinformatics analysis may help to define the pathogenesis and originate new treatments for MB.


2021 ◽  
Author(s):  
An Shuo Wang ◽  
Hao Xu ◽  
Ming Hui Zeng ◽  
Fei Wang

Abstract Background Non-functional pituitary adenoma (NFPA) is a disease with a high incidence, which accounts for a large part of pituitary tumors and plays a pivotal role. While invasive NFPAs which have not any endocrinology manifestations and space-occupying symptoms at early stages account for about 30 percent of NFPAs. The purpose of the present academic work was to identify significant genes with invasive promotion and their underlying mechanisms. Methods Gene expression profiles of GSE51618 was available from GEO database. There are 4 non-invasive NFPA tissues, 3 invasive NFPA tissues and 3 normal tissues in the profile datasets. Differentially expressed genes (DEGs) between non-invasive NFPA tissues and invasive NFPA tissues were picked out by GEO2R online tool. There were total of 226 up-regulated genes and 298 down-regulated genes. Next, we made use of the Database for Annotation, Visualization and Integrated Discovery (DAVID) to analyze Kyoto Encyclopedia of Gene and Genome (KEGG) pathway, gene ontology (GO) and Kaplan Meier Plotter. Then protein-protein interaction (PPI) of these DEGs was visualized by Cytoscape with Search Tool for the Retrieval of Interacting Genes (STRING). There were total of 141 up-regulated genes and 171 down-regulated genes. Of PPI network analyzed by Molecular Complex Detection (MCODE) plug-in, all 141 up-regulated genes were selected. Results After reanalysis of GO, five genes (ATP2B3, ADCYAP1R1, PTGER2, FSHβ, HTR4) were found to significantly enrich in the cAMP signaling pathway, Neuroactive ligand-receptor interaction and Renin secretion via reanalysis of DAVID. Conclusions We have identified five significant up-regulated DEGs with invasive promotion in invasive NFPAs on the basis of integrated bioinformatical methods, which could be potential therapeutic targets for invasive NFPAs patients.


2021 ◽  
Author(s):  
Zimeng Wei ◽  
Min Zhao ◽  
Linnan Zang

Abstract Background Lung adenocarcinoma (LUAD) is the main histological subtype of lung cancer. However, the molecular mechanism underlying LUAD is not yet clearly defined, but elucidating this process in detail would be of great significance for clinical diagnosis and treatment. Methods Gene expression profiles were retrieved from Gene Expression Omnibus database (GEO), and the common differentially expressed genes (DEGs) were identified by online GEO2R analysis tool. Subsequently, the enrichment analysis of function and signaling pathways of DEGs in LUAD were performed by gene ontology (GO) and The Kyoto Encyclopedia of Genes and Genomics (KEGG) analysis. The protein-protein interaction (PPI) networks of the DEGs were established through the Search Tool for the Retrieval of Interacting Genes (STRING) database and hub genes were screened by plug-in CytoHubba in Cytoscape. Afterwards, we detected the expression of hub genes in LUAD and other cancers via GEPIA, Oncomine and HPA databases. Finally, Kaplan-Meier plotter were performed to analyze the prognosis efficacy of hub genes. Results 74 up-regulated and 238 down-regulated DEGs were identified. As for the up-regulated DEGs, KEGG analysis results revealed they were mainly enrolled in protein digestion and absorption. However, the down-regulated DEGs were primarily enriched in cell adhesion molecules. Subsequently, 9 hub genes: KIAA0101, CDCA7, TOP2A, CDC20, ASPM, TPX2, CENPF, UBE2T and ECT2, were identified and showed higher expression in both LUAD and other cancers. Finally, all these hub genes were found significantly related to the prognosis of LUAD (p < 0.05). Conclusions Our results screened out the hub genes and pathways that were related to the development and prognosis of LUAD, which could provide new insight for the future molecularly targeted therapy and prognosis evaluation of LUAD.


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