Identification of key genes and associated pathways in neuroendocrine tumors through bioinformatics analysis and predictions of small drug molecules

AbstractNeuroendocrine tumor (NET) is one of malignant cancer and is identified with high morbidity and mortality rates around the world. With indigent clinical outcomes, potential biomarkers for diagnosis, prognosis and drug target are crucial to explore. The aim of this study is to examine the gene expression module of NET and to identify potential diagnostic and prognostic biomarkers as well as to find out new drug target. The differentially expressed genes (DEGs) identified from GSE65286 dataset was used for pathway enrichment analyses and gene ontology (GO) enrichment analyses and protein - protein interaction (PPI) analysis and module analysis. Moreover, miRNAs and transcription factors (TFs) that regulated the up and down regulated genes were predicted. Furthermore, validation of hub genes was performed. Finally, molecular docking studies were performed. DEGs were identified, including 453 down regulated and 459 up regulated genes. Pathway and GO enrichment analysis revealed that DEGs were enriched in sucrose degradation, creatine biosynthesis, anion transport and modulation of chemical synaptic transmission. Important hub genes and target genes were identified through PPI network, modules, target gene - miRNA network and target gene - TF network. Finally, survival analyses, receiver operating characteristic (ROC) curve and RT-PCR validated the significant difference of ATP1A1, LGALS3, LDHA, SYK, VDR, OBSL1, KRT40, WWOX, NINL and PPP2R2B between metastatic NET and normal controls. In conclusion, the DEGs and hub genes with their regulatory elements identified in this study will help us understand the molecular mechanisms underlying NET and provide candidate targets for future research.

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Identification of potential key genes and pathway linked with sporadic Creutzfeldt-Jakob disease based on integrated bioinformatics analyses

10.1101/2020.12.21.20248688 ◽

2020 ◽

Author(s):

Basavaraj Vastrad ◽

Chanabasayya Vastrad ◽

Iranna Kotturshetti

Keyword(s):

Regulatory Network ◽

Molecular Mechanisms ◽

Target Genes ◽

Enrichment Analysis ◽

Pathway Enrichment Analysis ◽

Ppi Network ◽

Hub Genes ◽

Bioinformatics Analyses ◽

Go Enrichment ◽

Jakob Disease

AbstractSporadic Creutzfeldt-Jakob disease (sCJD) is neurodegenerative disease also called prion disease linked with poor prognosis. The aim of the current study was to illuminate the underlying molecular mechanisms of sCJD. The mRNA microarray dataset GSE124571 was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened. Pathway and GO enrichment analyses of DEGs were performed. Furthermore, the protein-protein interaction (PPI) network was predicted using the IntAct Molecular Interaction Database and visualized with Cytoscape software. In addition, hub genes and important modules were selected based on the network. Finally, we constructed target genes - miRNA regulatory network and target genes - TF regulatory network. Hub genes were validated. A total of 891 DEGs 448 of these DEGs presented significant up regulated, and the remaining 443 down regulated were obtained. Pathway enrichment analysis indicated that up regulated genes were mainly linked with glutamine degradation/glutamate biosynthesis, while the down regulated genes were involved in melatonin degradation. GO enrichment analyses indicated that up regulated genes were mainly linked with chemical synaptic transmission, while the down regulated genes were involved in regulation of immune system process. hub and target genes were selected from the PPI network, modules, and target genes - miRNA regulatory network and target genes - TF regulatory network namely YWHAZ, GABARAPL1, EZR, CEBPA, HSPB8, TUBB2A and CDK14. The current study sheds light on the molecular mechanisms of sCJD and may provide molecular targets and diagnostic biomarkers for sCJD.

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Identification of potential core genes in hepatoblastoma via bioinformatics analysis

10.1101/2020.12.22.20248756 ◽

2020 ◽

Author(s):

Basavaraj Vastrad ◽

Chanabasayya Vastrad ◽

Iranna Kotturshetti

Keyword(s):

Gene Ontology ◽

Regulatory Network ◽

Target Gene ◽

Molecular Mechanisms ◽

Enrichment Analysis ◽

Metabolic Process ◽

Chromosome Organization ◽

Hub Genes ◽

Go Enrichment ◽

Go Enrichment Analysis

AbstractHepatoblastoma is the childhood liver cancer. Profound efforts have been made to illuminate the pathology, but the molecular mechanisms of hepatoblastoma are still not well understood. To identify the candidate genes in the carcinogenesis and progression of hepatoblastoma, microarray dataset GSE131329 was downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified, and pathway and Gene Ontology (GO) enrichment analysis were performed. The protein-protein interaction network (PPI), module analysis, target gene - miRNA regulatory network and target gene - TF regulatory network were constructed and analyzed. A total of 996 DEGs were identified, consisting of 499 up regulated genes and 497 down regulated genes. The pathway and Gene Ontology (GO) enrichment analysis of the DEGs include proline biosynthesis, superpathway of tryptophan utilization, chromosome organization and organic acid metabolic process. Twenty-four hub genes were identified and biological process analysis revealed that these genes were mainly enriched in cell cycle, chromosome organization, lipid metabolic process and oxidation-reduction process. Validation of hub genes showed that TP53, PLK1, AURKA, CDK1, ANLN, ESR1, FGB, ACAT1, GOT1 and ALAS1 may be involved in the carcinogenesis, invasion or recurrence of hepatoblastoma. In conclusion, DEGs and hub genes identified in the present study help us understand the molecular mechanisms underlying the carcinogenesis and progression of hepatoblastoma, and provide candidate targets for diagnosis and treatment of hepatoblastoma.

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Genome-wide miRNA profiling of villus and decidua of recurrent spontaneous abortion patients

Reproduction ◽

10.1530/rep-14-0095 ◽

2014 ◽

Vol 148 (1) ◽

pp. 33-41 ◽

Cited By ~ 48

Author(s):

Fulu Dong ◽

Yuan Zhang ◽

Fei Xia ◽

Yi Yang ◽

Sidong Xiong ◽

...

Keyword(s):

Spontaneous Abortion ◽

Molecular Mechanisms ◽

Target Genes ◽

Expression Profiles ◽

Normal Pregnancy ◽

Recurrent Spontaneous Abortion ◽

Future Research ◽

Rna Molecules ◽

Non Coding Rna ◽

Transcriptional Gene Regulation

MicroRNAs (miRNAs) are non-coding RNA molecules of about 22 nucleotides that involved in post-transcriptional gene regulation. Evidence indicates that miRNAs play essential roles in endometriosis, pre-eclampsia, infertility and other reproductive system diseases. However, whether miRNAs are involved in recurrent spontaneous abortion (RSA) is unclear. In this work, we analysed the miRNA expression profiles in six pairs of villus or decidua from RSA patients and normal pregnancy (NP) women using a human miRNA microarray. Some of the chip results were confirmed by RT-qPCR. In the villi of RSA patients, expression of hsa-miR-184, hsa-miR-187 and hsa-miR-125b-2 was significantly higher, while expression of hsa-miR-520f, hsa-miR-3175 and hsa-miR-4672 was significantly lower, comparing with those of NP control. As well, a total of five miRNAs (hsa-miR-517c, hsa-miR-519a-1, hsa-miR-522, hsa-miR-520h and hsa-miR-184) were upregulated in the decidua of RSA patients. The target genes of these differentially expressed miRNAs were predicted by miRWalk, and we speculate a network of miRNA regulating RSA by target genes function on adhesion, apoptosis and angiogenesis. Our study may help clarify the molecular mechanisms which are involved in the progression of RSA, and provide a reference for future research.

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Screening of cervical cancer-related hub genes based on comprehensive bioinformatics analysis

Cancer Biomarkers ◽

10.3233/cbm-203262 ◽

2021 ◽

pp. 1-13

Author(s):

Simei Tu ◽

Hao Zhang ◽

Xiaocheng Yang ◽

Wen Wen ◽

Kangjing Song ◽

...

Keyword(s):

Gene Expression ◽

Cervical Cancer ◽

Molecular Mechanisms ◽

Disease Free Survival ◽

The Cancer Genome Atlas ◽

Mrna Levels ◽

Hub Genes ◽

Normal Tissues ◽

Significant Difference ◽

Core Genes

BACKGROUND: Since the molecular mechanisms of cervical cancer (CC) have not been completely discovered, it is of great significance to identify the hub genes and pathways of this disease to reveal the molecular mechanisms of cervical cancer. OBJECTIVE: The study aimed to identify the biological functions and prognostic value of hub genes in cervical cancer. METHODS: The gene expression data of CC patients were downloaded from the Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA) database. The core genes were screened out by differential gene expression analysis and weighted gene co-expression network analysis (WGCNA). R software, the STRING online tool and Cytoscape software were used to screen out the hub genes. The GEPIA public database was used to further verify the expression levels of the hub genes in normal tissues and tumour tissues and determine the disease-free survival (DFS) rates of the hub genes. The protein expression of the survival-related hub genes was identified with the Human Protein Atlas (HPA) database. RESULTS: A total of 64 core genes were screened, and 10 genes, including RFC5, POLE3, RAD51, RMI1, PALB2, HDAC1, MCM4, ESR1, FOS and E2F1, were identified as hub genes. Compared with that in normal tissues, RFC5, POLE3, RAD51,RMI1, PALB2, MCM4 and E2F1 were all significantly upregulated in cervical cancer, ESR1 was significantly downregulated in cervical cancer, and high RFC5 expression in CC patients was significantly related to OS. In the DFS analysis, no significant difference was observed in the expression level of RFC5 in cervical cancer patients. Finally, RFC5 protein levels verified by the HPA database were consistently upregulated with mRNA levels in CC samples. CONCLUSIONS: RFC5 may play important roles in the occurrence and prognosis of CC. It could be further explored and validated as a potential predictor and therapeutic target for CC.

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Identification and Classification of Hubs in microRNA Target Gene Networks in Human Neural Stem/Progenitor Cells following Japanese Encephalitis Virus Infection

mSphere ◽

10.1128/msphere.00588-19 ◽

2019 ◽

Vol 4 (5) ◽

Author(s):

Sriparna Mukherjee ◽

Irshad Akbar ◽

Reshma Bhagat ◽

Bibhabasu Hazra ◽

Arindam Bhattacharyya ◽

...

Keyword(s):

Progenitor Cells ◽

Gene Networks ◽

Mirna Target ◽

Target Gene ◽

Target Genes ◽

Hub Genes ◽

Protein Protein Interaction ◽

Ppi Networks ◽

Neural Stem Progenitor Cells

ABSTRACT RNA viruses are known to modulate host microRNA (miRNA) machinery for their own benefit. Japanese encephalitis virus (JEV), a neurotropic RNA virus, has been reported to manipulate several miRNAs in neurons or microglia. However, no report indicates a complete sketch of the miRNA profile of neural stem/progenitor cells (NSPCs), hence the focus of our current study. We used an miRNA array of 84 miRNAs in uninfected and JEV-infected human neuronal progenitor cells and primary neural precursor cells isolated from aborted fetuses. Severalfold downregulation of hsa-miR-9-5p, hsa-miR-22-3p, hsa-miR-124-3p, and hsa-miR-132-3p was found postinfection in both of the cell types compared to the uninfected cells. Subsequently, we screened for the target genes of these miRNAs and looked for the biological pathways that were significantly regulated by the genes. The target genes involved in two or more pathways were sorted out. Protein-protein interaction (PPI) networks of the miRNA target genes were formed based on their interaction patterns. A binary adjacency matrix for each gene network was prepared. Different modules or communities were identified in those networks by community detection algorithms. Mathematically, we identified the hub genes by analyzing their degree centrality and participation coefficient in the network. The hub genes were classified as either provincial (P < 0.4) or connector (P > 0.4) hubs. We validated the expression of hub genes in both cell line and primary cells through qRT-PCR after JEV infection and respective miR mimic transfection. Taken together, our findings highlight the importance of specific target gene networks of miRNAs affected by JEV infection in NSPCs. IMPORTANCE JEV damages the neural stem/progenitor cell population of the mammalian brain. However, JEV-induced alteration in the miRNA expression pattern of the cell population remains an open question, hence warranting our present study. In this study, we specifically address the downregulation of four miRNAs, and we prepared a protein-protein interaction network of miRNA target genes. We identified two types of hub genes in the PPI network, namely, connector hubs and provincial hubs. These two types of miRNA target hub genes critically influence the participation strength in the networks and thereby significantly impact up- and downregulation in several key biological pathways. Computational analysis of the PPI networks identifies key protein interactions and hubs in those modules, which opens up the possibility of precise identification and classification of host factors for viral infection in NSPCs.

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Integration and Visualization of Regulatory Elements and Variations of the EPAS1 Gene in Human

Genes ◽

10.3390/genes12111793 ◽

2021 ◽

Vol 12 (11) ◽

pp. 1793

Author(s):

Aleša Kristan ◽

Nataša Debeljak ◽

Tanja Kunej

Keyword(s):

Target Genes ◽

Regulatory Elements ◽

Future Research ◽

Protein Abundance ◽

Interacting Proteins ◽

Pas Domain ◽

Expression Stability ◽

Post Translational Modifications ◽

Oxygen Homeostasis ◽

Cancer Types

Endothelial PAS domain-containing protein 1 (EPAS1), also HIF2α, is an alpha subunit of hypoxia-inducible transcription factor (HIF), which mediates cellular and systemic response to hypoxia. EPAS1 has an important role in the transcription of many hypoxia-responsive genes, however, it has been less researched than HIF1α. The aim of this study was to integrate an increasing number of data on EPAS1 into a map of diverse OMICs elements. Publications, databases, and bioinformatics tools were examined, including Ensembl, MethPrimer, STRING, miRTarBase, COSMIC, and LOVD. The EPAS1 expression, stability, and activity are tightly regulated on several OMICs levels to maintain complex oxygen homeostasis. In the integrative EPAS1 map we included: 31 promoter-binding proteins, 13 interacting miRNAs and one lncRNA, and 16 post-translational modifications regulating EPAS1 protein abundance. EPAS1 has been associated with various cancer types and other diseases. The development of neuroendocrine tumors and erythrocytosis was shown to be associated with 11 somatic and 20 germline variants. The integrative map also includes 12 EPAS1 target genes and 27 interacting proteins. The study introduced the first integrative map of diverse genomics, transcriptomics, proteomics, regulomics, and interactomics data associated with EPAS1, to enable a better understanding of EPAS1 activity and regulation and support future research.

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Elevation of MicroRNA-126 Levels in Intracranial Aneurysm and Bioinformatic Analysis of Potential Molecular Mechanisms

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2021.2572 ◽

2021 ◽

Vol 11 (4) ◽

pp. 573-579

Author(s):

Pan Huang ◽

Min Xu ◽

Xiao-Ying He

Keyword(s):

Intracranial Aneurysm ◽

Peripheral Blood ◽

Target Gene ◽

Molecular Mechanisms ◽

Target Genes ◽

Kegg Pathway ◽

Bioinformatic Analysis ◽

Control Group ◽

Potential Target ◽

Fas Signaling

The study is to investigation of microRNA-126 levels in patients with intracranial aneurysm and bioinformatic analysis of the molecular mechanisms involved. A total of 166 patients with ICA who were hospitalized or examined in our hospital from September 2015 to December 2017 were used as the experimental group (ICA group). This group included 120 patients with unruptured intracranial aneurysm (UICA; UICA group) and 46 patients with ruptured intracranial aneurysm (RICA); RICA group). The UICA group was further subdivided into 42 surgical groups (S group) and 78 nonsurgical groups (NS group). Sixty-three normal people without intracranial aneurysms were selected as the control group. RT-PCR was used to quantitatively detect the relative expression of microRNA- 126 in peripheral blood mononuclear cells at the time of admission and immediately after surgery. The UCSC database was used to analyze the gene locus and homology of microRNA-126. The TargetScan database and CoMeTa database were used to predict the potential target genes of microRNA-126. The DAVID database was used to enrich the function of potential target genes of microRNA-126 (GO enrichment) and KEGG pathway enrichment for analysis. The expression level of microRNA-126 in peripheral blood was significantly higher in the ICA group than in the control group (P <0.01), significantly higher in the RICA group than in the UICA group (P <0.05). Expression was also higher in the NS group than in the S group but the difference was nonsignificant (P >0.05). A total of 15 potential target genes including ITGA6, CRK, PCDH7, and ADAM9 were identified through the target gene prediction software and GO analysis and KEGG pathway analysis showed that the function of the microRNA-126 target gene was mainly focused on protein binding and the FAS signaling pathway. In Conclusion the microRNA-126 is up-regulated in ICA patients and affects ICA by regulating multiple target genes in the FAS signaling pathway.

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Transcriptome Signatures Reveal Candidate Key Genes in the Peripheral Blood Mononuclear Cells of Patients With Coronary Artery Disease

10.21203/rs.3.rs-122558/v1 ◽

2020 ◽

Author(s):

Vijayakrishna Kolur ◽

Basavaraj Vastrad ◽

Chanabasayya Vastrad ◽

Iranna Kotturshetti ◽

Anandkumar Tengli

Keyword(s):

Coronary Artery Disease ◽

Gene Ontology ◽

Coronary Artery ◽

Regulatory Network ◽

Target Gene ◽

Enrichment Analysis ◽

Hub Genes ◽

Go Enrichment ◽

Artery Disease ◽

Go Enrichment Analysis

Abstract BackgroundCoronary artery disease (CAD) is one of the most common disorders in the cardiovascular system. This study aims to explore potential signaling pathways and important biomarkers that drive CAD development. MethodsThe CAD GEO Dataset GSE113079 was featured to screen differentially expressed genes (DEGs). The pathway and Gene Ontology (GO) enrichment analysis of DEGs were analyzed using the ToppGene. We screened hub and target genes from protein-protein interaction (PPI) networks, target gene - miRNA regulatory network and target gene - TF regulatory network, and Cytoscape software. Validations of hub genes were performed to evaluate their potential prognostic and diagnostic value for CAD. Results1,036 DEGs were captured according to screening criteria (525upregulated genes and 511downregulated genes). Pathway and Gene Ontology (GO) enrichment analysis of DEGs revealed that these up and down regulated genes are mainly enriched in thyronamine and iodothyronamine metabolism, cytokine-cytokine receptor interaction, nervous system process, cell cycle and nuclear membrane. Hub genes were validated to find out potential prognostic biomarkers, diagnostic biomarkers and novel therapeutic target for CAD. ConclusionsIn summary, our findings discovered pivotal gene expression signatures and signaling pathways in the progression of CAD. CAPN13, ACTBL2, ERBB3, GATA4, GNB4, NOTCH2, EXOSC10, RNF2, PSMA1 and PRKAA1 might contribute to the progression of CAD, which could have potential as biomarkers or therapeutic targets for CAD.

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KAP1-associated transcriptional inhibitory complex regulates C2C12 myoblasts differentiation and mitochondrial biogenesis via miR-133a repression

Cell Death and Disease ◽

10.1038/s41419-020-02937-5 ◽

2020 ◽

Vol 11 (9) ◽

Author(s):

Jialing Zhang ◽

Chaoju Hua ◽

Yu Zhang ◽

Peng Wei ◽

Yaping Tu ◽

...

Keyword(s):

Cell Differentiation ◽

Molecular Mechanisms ◽

Target Genes ◽

Affinity Purification ◽

Regulatory Elements ◽

C2c12 Myoblasts ◽

Regulatory Machinery ◽

New Ideas ◽

Biogenesis Of Mitochondria

Abstract The differentiation of myoblasts plays a key role in the growth of biological individuals and the reconstruction of muscle tissue. Several microRNAs are significantly upregulated during the differentiation of myoblasts and their target genes have been explored. However, the molecular mechanisms underlying the transcriptional regulation of microRNAs remain elusive. In the present study, we found that the expression of miR-133a is increased during the differentiation of C2C12 myoblasts. miR-133a mimic is sufficient to induce the biogenesis of mitochondria and differentiation of C2C12 myoblasts whereas miR-133a inhibitor abolishes cell differentiation. Using CRISPR affinity purification in situ of regulatory elements (CAPTURE) technique, we further dissected the regulatory mechanisms of miR-133a expression and found that KAP1-associated transcription complex accounts for the suppression of miR-133a in C2C12 myoblasts. Knockdown of KAP1 increased the expression of miR-133a, which contributed to the biogenesis of mitochondria and differentiation of C2C12 myoblasts. To our knowledge, this is the first study using the CAPTURE technology to identify the regulatory factors of miR-133a during cell differentiation, which may provide new ideas for understanding the precision regulatory machinery of microRNAs during different biological processes.

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A Network Pharmacology-Based Study on the Anti-Lung Cancer Effect of Dipsaci Radix

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/7424061 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Jiayan Wu ◽

Shengkun Hong ◽

Xiankuan Xie ◽

Wangmi Liu

Keyword(s):

Lung Cancer ◽

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Molecular Mechanisms ◽

Target Genes ◽

Interaction Network ◽

Network Pharmacology ◽

Pathway Enrichment Analysis ◽

Hub Genes ◽

Active Compounds

Objective. Dipsaci Radix (DR) has been used to treat fracture and osteoporosis. Recent reports have shown that myeloid cells from bone marrow can promote the proliferation of lung cancer. However, the action and mechanism of DR has not been well defined in lung cancer. The aim of the present study was to define molecular mechanisms of DR as a potential therapeutic approach to treat lung cancer. Methods. Active compounds of DR with oral bioavailability ≥30% and drug-likeness index ≥0.18 were obtained from the traditional Chinese medicine systems pharmacology database and analysis platform. The potential target genes of the active compounds and bone were identified by PharmMapper and GeneCards, respectively. The compound-target network and protein-protein interaction network were built by Cytoscape software and Search Tool for the Retrieval of Interacting Genes webserver, respectively. GO analysis and pathway enrichment analysis were performed using R software. Results. Our study demonstrated that DR had 6 active compounds, including gentisin, sitosterol, Sylvestroside III, 3,5-Di-O-caffeoylquinic acid, cauloside A, and japonine. There were 254 target genes related to these active compounds as well as to bone. SRC, AKT1, and GRB2 were the top 3 hub genes. Metabolisms and signaling pathways associated with these hub genes were significantly enriched. Conclusions. This study indicated that DR could exhibit the anti-lung cancer effect by affecting multiple targets and multiple pathways. It reflects the traditional Chinese medicine characterized by multicomponents and multitargets. DR could be considered as a candidate for clinical anticancer therapy by regulating bone physiological functions.

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