scholarly journals High Expression of BCL11A Predicts Poor Prognosis for Childhood MLL-r ALL

2021 ◽  
Vol 11 ◽  
Author(s):  
Lu-Lu Wang ◽  
Dehong Yan ◽  
Xue Tang ◽  
Mengqi Zhang ◽  
Shilin Liu ◽  
...  

BackgroundDespite much improvement in the treatment for acute lymphoblastic leukemia (ALL), childhood ALLs with MLL-rearrangement (MLL-r) still have inferior dismal prognosis. Thus, defining mechanisms underlying MLL-r ALL maintenance is critical for developing effective therapy.MethodsGSE13159 and GSE28497 were selected via the Oncomine website. Differentially expressed genes (DEGs) between MLL-r ALLs and normal samples were identified by R software. Next, functional enrichment analysis of these DEGs were carried out by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). Then, the key hub genes and modules were identified by Weighted Gene Co-expression Network Analysis (WGCNA). Therapeutically Applicable Research to Generate Effective Treatments (TARGET) ALL (Phase I) of UCSC Xena analysis, qPCR, and Kaplan-Meier analysis were conducted for validating the expression of key hub genes from bone marrow cells of childhood ALL patients or ALL cell lines.ResultsA total of 1,045 DEGs were identified from GSE13159 and GSE28497. Through GO, KEGG, GSEA, and STRING analysis, we demonstrated that MLL-r ALLs were upregulating “nucleosome assembly” and “B cell receptor signal pathway” genes or proteins. WGCNA analysis found 18 gene modules using hierarchical clustering between MLL-r ALLs and normal. The Venn diagram was used to filter the 98 hub genes found in the key module with the 1,045 DEGs. We identified 18 hub genes from this process, 9 of which were found to be correlated with MLL-r status, using the UCSC Xena analysis. By using qPCR, we validated these 9 hub key genes to be upregulated in the MLL-r ALLs (RS4;11 and SEM) compared to the non-MLL-r ALL (RCH-ACV) cell lines. Three of these genes, BCL11A, GLT8D1 and NCBP2, were shown to be increased in MLL-r ALL patient bone marrows compared to the non-MLL-r ALL patient. Finally, Kaplan–Meier analysis indicated that childhood ALL patients with high BCL11A expression had significantly poor overall survival.ConclusionThese findings suggest that upregulated BCL11A gene expression in childhood ALLs may lead to MLL-r ALL development and BCL11A represents a new potential therapeutic target for childhood MLL-r ALL.

2021 ◽  
Vol 22 (12) ◽  
pp. 6505
Author(s):  
Jishizhan Chen ◽  
Jia Hua ◽  
Wenhui Song

Applying mesenchymal stem cells (MSCs), together with the distraction osteogenesis (DO) process, displayed enhanced bone quality and shorter treatment periods. The DO guides the differentiation of MSCs by providing mechanical clues. However, the underlying key genes and pathways are largely unknown. The aim of this study was to screen and identify hub genes involved in distraction-induced osteogenesis of MSCs and potential molecular mechanisms. Material and Methods: The datasets were downloaded from the ArrayExpress database. Three samples of negative control and two samples subjected to 5% cyclic sinusoidal distraction at 0.25 Hz for 6 h were selected for screening differentially expressed genes (DEGs) and then analysed via bioinformatics methods. The Gene Ontology (GO) terms and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment were investigated. The protein–protein interaction (PPI) network was visualised through the Cytoscape software. Gene set enrichment analysis (GSEA) was conducted to verify the enrichment of a self-defined osteogenic gene sets collection and identify osteogenic hub genes. Results: Three hub genes (IL6, MMP2, and EP300) that were highly associated with distraction-induced osteogenesis of MSCs were identified via the Venn diagram. These hub genes could provide a new understanding of distraction-induced osteogenic differentiation of MSCs and serve as potential gene targets for optimising DO via targeted therapies.


2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Xiang Qian ◽  
Zhuo Chen ◽  
Sha Sha Chen ◽  
Lu Ming Liu ◽  
Ai Qin Zhang

The study aimed to clarify the potential immune-related targets and mechanisms of Qingyihuaji Formula (QYHJ) against pancreatic cancer (PC) through network pharmacology and weighted gene co-expression network analysis (WGCNA). Active ingredients of herbs in QYHJ were identified by the TCMSP database. Then, the putative targets of active ingredients were predicted with SwissTargetPrediction and the STITCH databases. The expression profiles of GSE32676 were downloaded from the GEO database. WGCNA was used to identify the co-expression modules. Besides, the putative targets, immune-related targets, and the critical module genes were mapped with the specific disease to select the overlapped genes (OGEs). Functional enrichment analysis of putative targets and OGEs was conducted. The overall survival (OS) analysis of OGEs was investigated using the Kaplan-Meier plotter. The relative expression and methylation levels of OGEs were detected in UALCAN, human protein atlas (HPA), Oncomine, DiseaseMeth version 2.0 and, MEXPRESS database, respectively. Gene set enrichment analysis (GSEA) was conducted to elucidate the key pathways of highly-expressed OGEs further. OS analyses found that 12 up-regulated OGEs, including CDK1, PLD1, MET, F2RL1, XDH, NEK2, TOP2A, NQO1, CCND1, PTK6, CTSE, and ERBB2 that could be utilized as potential diagnostic indicators for PC. Further, methylation analyses suggested that the abnormal up-regulation of these OGEs probably resulted from hypomethylation, and GSEA revealed the genes markedly related to cell cycle and proliferation of PC. This study identified CDK1, PLD1, MET, F2RL1, XDH, NEK2, TOP2A, NQO1, CCND1, PTK6, CTSE, and ERBB2 might be used as reliable immune-related biomarkers for prognosis of PC, which may be essential immunotherapies targets of QYHJ.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Huan Deng ◽  
Qingqing Hang ◽  
Dijian Shen ◽  
Yibi Zhang ◽  
Ming Chen

Abstract Purpose Exploring the molecular mechanisms of lung adenocarcinoma (LUAD) is beneficial for developing new therapeutic strategies and predicting prognosis. This study was performed to select core genes related to LUAD and to analyze their prognostic value. Methods Microarray datasets from the GEO (GSE75037) and TCGA-LUAD datasets were analyzed to identify differentially coexpressed genes in LUAD using weighted gene coexpression network analysis (WGCNA) and differential gene expression analysis. Functional enrichment analysis was conducted, and a protein–protein interaction (PPI) network was established. Subsequently, hub genes were identified using the CytoHubba plug-in. Overall survival (OS) analyses of hub genes were performed. The Clinical Proteomic Tumor Analysis Consortium (CPTAC) and the Human Protein Atlas (THPA) databases were used to validate our findings. Gene set enrichment analysis (GSEA) of survival-related hub genes were conducted. Immunohistochemistry (IHC) was carried out to validate our findings. Results We identified 486 differentially coexpressed genes. Functional enrichment analysis suggested these genes were primarily enriched in the regulation of epithelial cell proliferation, collagen-containing extracellular matrix, transforming growth factor beta binding, and signaling pathways regulating the pluripotency of stem cells. Ten hub genes were detected using the maximal clique centrality (MCC) algorithm, and four genes were closely associated with OS. The CPTAC and THPA databases revealed that CHRDL1 and SPARCL1 were downregulated at the mRNA and protein expression levels in LUAD, whereas SPP1 was upregulated. GSEA demonstrated that DNA-dependent DNA replication and catalytic activity acting on RNA were correlated with CHRDL1 and SPARCL1 expression, respectively. The IHC results suggested that CHRDL1 and SPARCL1 were significantly downregulated in LUAD. Conclusions Our study revealed that survival-related hub genes closely correlated with the initiation and progression of LUAD. Furthermore, CHRDL1 and SPARCL1 are potential therapeutic and prognostic indicators of LUAD.


2019 ◽  
Vol 39 (7) ◽  
Author(s):  
Yadong Wu ◽  
Feng liu ◽  
Siyang Luo ◽  
Xinhai Yin ◽  
Dengqi He ◽  
...  

Abstract Breast cancer (BC) is the most common leading cause of cancer-related death in women worldwide. Gene expression profiling analysis for human BCs has been studied previously. However, co-expression analysis for BC cell lines is still devoid to date. The aim of the study was to identify key pathways and hub genes that may serve as a biomarker for BC and uncover potential molecular mechanism using weighted correlation network analysis. We analyzed microarray data of BC cell lines (GSE 48213) listed in the Gene Expression Omnibus database. Gene co-expression networks were used to construct and explore the biological function in hub modules using the weighted correlation network analysis algorithm method. Meanwhile, Gene ontology and KEGG pathway analysis were performed using Cytoscape plug-in ClueGo. The network of the key module was also constructed using Cytoscape. A total of 5000 genes were selected, 28 modules of co-expressed genes were identified from the gene co–expression network, one of which was found to be significantly associated with a subtype of BC lines. Functional enrichment analysis revealed that the brown module was mainly involved in the pathway of the autophagy, spliceosome, and mitophagy, the black module was mainly enriched in the pathway of colorectal cancer and pancreatic cancer, and genes in midnightblue module played critical roles in ribosome and regulation of lipolysis in adipocytes pathway. Three hub genes CBR3, SF3B6, and RHPN1 may play an important role in the development and malignancy of the disease. The findings of the present study could improve our understanding of the molecular pathogenesis of breast cancer.


2021 ◽  
Author(s):  
Liuxun Li ◽  
Xiaokang Du ◽  
Haiqian Ling ◽  
Yuhang Li ◽  
Xuemin Wu ◽  
...  

Abstract Background: Sciatic nerve injury (SNI), which frequently occurs under the traumatic hip and hip fracture dislocation, induces serious complications such as motor and sensory loss, muscle atrophy, or even disabling. The present work aimed to determine the regulating factors and gene network related to the SNI pathology.Methods: Sciatic nerve injury dataset GSE18803 with 24 samples was randomly divided into adult group and neonate group. We performed weighted gene co-expression network analysis (WGCNA) to identify modules associated with SNI in the two groups. Moreover, differentially expressed genes (DEGs) were determined from every group, separately. Subsequently, co-expression network, protein-protein interaction (PPI) network, enrichment analysis and gene set enrichment analysis (GSEA) were integrated to identify hub genes and associated pathways. GSE30165 was used as the test set for investigating the hub gene involvement within SNI. Finally, we employed DGIdb for predicting the possible therapeutic agents leading to the abnormal up-regulation of hub genes.Results: 14 SNI status modules and 97 DEGs were identified in adult group, while 15 modules and 21 DEGs in neonate group. A total of 12 hub genes was overlapping from co-expression and PPI network. After the results from both test and training sets were overlapped, we verified that the ten real hub genes showed remarkably up-regulation within SNI. According to functional enrichment of DEGs, the above genes participated in the immune effector process, inflammatory responses, the antigen processing and presentation, and the phagocytosis. GSEA also supported that gene sets with the highest significance was mostly related to the cytokine-cytokine receptor interaction.Conclusions: The gene expression network is determined in the present work based on the related regulating factors within SNI, which sheds more lights on SNI pathology and offers the possible biomarkers and therapeutic targets in subsequent research.


2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Chengzhang Li ◽  
Jiucheng Xu

AbstractThis study aimed to select the feature genes of hepatocellular carcinoma (HCC) with the Fisher score algorithm and to identify hub genes with the Maximal Clique Centrality (MCC) algorithm. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed to examine the enrichment of terms. Gene set enrichment analysis (GSEA) was used to identify the classes of genes that are overrepresented. Following the construction of a protein-protein interaction network with the feature genes, hub genes were identified with the MCC algorithm. The Kaplan–Meier plotter was utilized to assess the prognosis of patients based on expression of the hub genes. The feature genes were closely associated with cancer and the cell cycle, as revealed by GO, KEGG and GSEA enrichment analyses. Survival analysis showed that the overexpression of the Fisher score–selected hub genes was associated with decreased survival time (P < 0.05). Weighted gene co-expression network analysis (WGCNA), Lasso, ReliefF and random forest were used for comparison with the Fisher score algorithm. The comparison among these approaches showed that the Fisher score algorithm is superior to the Lasso and ReliefF algorithms in terms of hub gene identification and has similar performance to the WGCNA and random forest algorithms. Our results demonstrated that the Fisher score followed by the application of the MCC algorithm can accurately identify hub genes in HCC.


2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Mingshuang Li ◽  
Conglin Ren ◽  
Chenxia Wu ◽  
Xinyao Li ◽  
Xinyi Li ◽  
...  

Background. Acute coronary syndrome (ACS) has a high incidence and mortality rate. Early detection and intervention would provide clinical benefits. This study aimed to reveal hub genes, transcription factors (TFs), and microRNAs (miRNAs) that affect plaque stability and provide the possibility for the early diagnosis and treatment of ACS. Methods. We obtained gene expression matrix GSE19339 for ACS patients and healthy subjects from public database. The differentially expressed genes (DEGs) were screened using Limma package in R software. The biological functions of DEGs were shown by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). Protein-protein interaction (PPI) network was mapped in Cytoscape, followed by screening of hub genes based on the Molecular Complex Detection (MCODE) plug-in. Functional Enrichment analysis tool (FunRich) and Database for Annotation, Visualization and Integrated Discovery (DAVID) were used to predict miRNAs and TFs, respectively. Finally, GSE60993 expression matrix was chosen to plot receiver operating characteristic (ROC) curves with the aim of further assessing the reliability of our findings. Results. We obtained 176 DEGs and further identified 16 hub genes by MCODE. The results of functional enrichment analysis showed that DEGs mediated inflammatory response and immune-related pathways. Among the predicted miRNAs, hsa-miR-4770, hsa-miR-5195, and hsa-miR-6088 all possessed two target genes, which might be closely related to the development of ACS. Moreover, we identified 11 TFs regulating hub gene transcriptional processes. Finally, ROC curves confirmed three genes with high confidence (area under the curve > 0.9), including VEGFA, SPP1, and VCAM1. Conclusion. This study suggests that three genes (VEGFA, SPP1, and VCAM1) were involved in the molecular mechanisms of ACS pathogenesis and could serve as biomarkers of disease progression.


2021 ◽  
Vol 12 ◽  
Author(s):  
Zhengze Shen ◽  
Shengwei Liu ◽  
Jie Liu ◽  
Jingdong Liu ◽  
Caoyuan Yao

Despite the recent progress of lung adenocarcinoma (LUAD) therapy, tumor recurrence remained to be a challenging factor that impedes the effectiveness of treatment. The objective of the present study was to predict the hub genes affecting LUAD recurrence via weighted gene co-expression network analysis (WGCNA). Microarray samples from LUAD dataset of GSE32863 were analyzed, and the modules with the highest correlation to tumor recurrence were selected. Functional enrichment analysis was conducted, followed by establishment of a protein–protein interaction (PPI) network. Subsequently, hub genes were identified by overall survival analyses and further validated by evaluation of expression in both myeloid populations and tissue samples of LUAD. Gene set enrichment analysis (GSEA) was then carried out, and construction of transcription factors (TF)–hub gene and drug–hub gene interaction network was also achieved. A total of eight hub genes (ACTR3, ARPC5, RAB13, HNRNPK, PA2G4, WDR12, SRSF1, and NOP58) were finally identified to be closely correlated with LUAD recurrence. In addition, TFs that regulate hub genes have been predicted, including MYC, PML, and YY1. Finally, drugs including arsenic trioxide, cisplatin, Jinfukang, and sunitinib were mined for the treatment of the eight hub genes. In conclusion, our study may facilitate the invention of targeted therapeutic drugs and shed light on the understanding of the mechanism for LUAD recurrence.


2020 ◽  
Author(s):  
Chao Yuan ◽  
Hongjun Yuan ◽  
Li Chen ◽  
Miaomiao Sheng ◽  
Wenru Tang

Abstract Background:Triple-negative breast cancer (TNBC) is an essential type of breast cancer (BC). Compared with other molecular subtypes of BC, TNBC has the features of fast tumor increase, quick recurrence and natural metastasis. It is more urgent to establish a comprehensive evaluation system containing multiple biomarkers than single parameter.Methods:We conduct a bioinformatics analysis on 13 BC expression datasets from the Gene Expression Omnibus (GEO), which covered 2950 samples. We took 3484 genes with a more significant difference between TNBC and normal-like candidate genes for weighted correlation network analysis (WGCNA). A total of 54 genes were chosen as hub genes with great connectivity with the TNBC significant module. Based on The Cancer Genome Atlas (TCGA) data, we identify the best prognostic three lncRNA. Multivariate Cox regression was used to construct a 3-lncRNA risk score model. We evaluated prognostic capacity using time-dependent subject operating characteristics (ROC) and Kaplan-Meier (KM) survival analysis. The predictive power of the model was demonstrated by the time-dependent ROC spline and Kaplan-Meier spline. At the same time, it also shows good predictive ability in the validation set. Ultimately, Functional enrichment analysis of hub genes and three lncRNAs were offered to advise the possible biological pathways. Results:The construct LNC00337, DEPCE-AS1, DDX11-AS1 multi-factor risk scoring model was meaningfully associated with the prognosis of TNBC patients. Through survival analysis, the risk score efficiently divided the patients into high-risk groups with poor overall survival. The time-dependent ROC curve revealed that the model presented robust in predicting survival over the first 3 years. The validity of the model in the validation set is also verified. Finally, functional enrichment analysis proposed some biological pathways that may be correlated to the tumor. Conclusions:In our study, we established a lncRNA-based model to prognosticate the prediction of TNBC, which might afford a strong prognosis estimate tool to help therapy policy-making in the clinic.


2021 ◽  
Vol 2021 ◽  
pp. 1-25
Author(s):  
Tian-ming Huo ◽  
Zhi-wei Wang

Background. The study was aimed at finding accurate and effective therapeutic targets and deepening our understanding of the mechanisms of advanced atherosclerosis (AA). Methods. We downloaded the gene expression datasets GSE28829, GSE120521, and GSE43292 from Gene Expression Omnibus. Weighted gene coexpression network analysis (WGCNA) was performed for GSE28829, and functional enrichment analysis and protein–protein interaction network analysis were conducted on the key module. Significant genes in the key module were analyzed by molecular complex detection, and genes in the most important subnetwork were defined as hub genes. Multiple dataset analyses for hub genes were conducted. Genes that overlapped between hub genes and differentially expressed genes (DEGs) of GSE28829 and GSE120521 were defined as key genes. Further validation for key genes was performed using GSE28829 and GSE43292. Gene set enrichment analysis (GSEA) was applied to key genes. Results. A total of 77 significant genes in the key module of GSE28829 were screened out that were mainly associated with inflammation and immunity. The subnetwork was obtained from significant genes, and 18 genes in this module were defined as hub genes, which were related to immunity and expressed in multiple diseases, particularly systemic lupus erythematosus. Some hub genes were regulated by SPI1 and associated with the blood, spleen, and lung. After overlapping with DEGs of GSE28829 and GSE120521, a total of 10 genes (HCK, ITGAM, CTSS, TYROBP, LAPTM5, FCER1G, ITGB2, NCF2, AIF1, and CD86) were identified as key genes. All key genes were validated and evaluated successfully and were related to immune response pathways. Conclusion. Our study suggests that the key genes related to immune and inflammatory responses are involved in the development of AA. This may deepen our understanding of the mechanisms of and provide valuable therapeutic targets for AA.


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