HPV-associated penile cancer: Impact of copy number alterations in miRNA/mRNA interactions and potential druggable targets

2021 ◽  
pp. 1-14
Author(s):  
Jenilson da Silva ◽  
Leudivan Nogueira ◽  
Ronald Coelho ◽  
Amanda Deus ◽  
André Khayat ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Copy Number ◽  
Drug Targets ◽  
Penile Cancer ◽  
Target Genes ◽  
Kegg Pathways ◽  
Mrna Targets ◽  
Genome Wide ◽  
Target Treatment ◽  
Druggable Targets

BACKGROUND: Penile cancer (PeCa) is a rare disease, but its incidence has increased worldwide, mostly in HPV+ patients. Nevertheless, there is still no targeted treatment for this carcinoma. OBJECTIVE: To predict the main signaling pathways involved in penile tumorigenesis and its potential drug targets. METHODS: Genome-wide copy number profiling was performed in 28 PeCa. Integration analysis of CNAs and miRNAs and mRNA targets was performed by DIANA-TarBase v.8. The potential impact of the miRNAs/target genes on biological pathways was assessed by DIANA-miRPath v.3.0. For each miRNA, KEGG pathways were generated based on the tarbase and microT-CDS algorithms. Pharmaco-miR was used to identify associations between miRNAs and their target genes to predict druggable targets. RESULTS: 269 miRNAs and 2,395 genes were mapped in cytobands with CNAs. The comparison of the miRNAs mapped at these cytobands and the miRNAs that were predicted to regulate the genes also mapped in these regions, resulted in a set of common 35 miRNAs and 292 genes. Enrichment pathway revealed their involvement in five top signaling pathways. EGFR and COX2 were identified as potential druggable targets. CONCLUSION: Our data indicate the potential use of EGFR and COX2 inhibitors as a target treatment for PeCa patients.

scholarly journals Dysregulation of post-transcriptional modification by copy number variable microRNAs in schizophrenia with enhanced glycation stress

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Akane Yoshikawa ◽  
Itaru Kushima ◽  
Mitsuhiro Miyashita ◽  
Kazuya Toriumi ◽  
Kazuhiro Suzuki ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Copy Number ◽  
Mirna Target ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Synaptic Function ◽  
Gene Set Enrichment Analysis ◽  
Gene Set Enrichment ◽  
Gene Set ◽  
Genome Wide

AbstractPreviously, we identified a subpopulation of schizophrenia (SCZ) showing increased levels of plasma pentosidine, a marker of glycation and oxidative stress. However, its causative genetic factors remain largely unknown. Recently, it has been suggested that dysregulated posttranslational modification by copy number variable microRNAs (CNV-miRNAs) may contribute to the etiology of SCZ. Here, an integrative genome-wide CNV-miRNA analysis was performed to investigate the etiology of SCZ with accumulated plasma pentosidine (PEN-SCZ). The number of CNV-miRNAs and the gene ontology (GO) in the context of miRNAs within CNVs were compared between PEN-SCZ and non-PEN-SCZ groups. Gene set enrichment analysis of miRNA target genes was further performed to evaluate the pathways affected in PEN-SCZ. We show that miRNAs were significantly enriched within CNVs in the PEN-SCZ versus non-PEN-SCZ groups (p = 0.032). Of note, as per GO analysis, the dysregulated neurodevelopmental events in the two groups may have different origins. Additionally, gene set enrichment analysis of miRNA target genes revealed that miRNAs involved in glycation/oxidative stress and synaptic neurotransmission, especially glutamate/GABA receptor signaling, were possibly affected in PEN-SCZ. To the best of our knowledge, this is the first genome-wide CNV-miRNA study suggesting the role of CNV-miRNAs in the etiology of PEN-SCZ, through effects on genes related to glycation/oxidative stress and synaptic function. Our findings provide supportive evidence that glycation/oxidative stress possibly caused by genetic defects related to the posttranscriptional modification may lead to synaptic dysfunction. Therefore, targeting miRNAs may be one of the promising approaches for the treatment of PEN-SCZ.

Genome-Wide Analysis of Copy Number Analysis of Myelodysplastic Syndromes Using High-Density SNP-Genotyping Microarrays.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3420-3420
Author(s):  
Masashi Sanada ◽  
Yasuhito Nannya ◽  
Kumi Nakazaki ◽  
Go Yamamoto ◽  
Lili Wang ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Copy Number ◽  
Large Scale ◽  
Target Genes ◽  
Chromosomal Abnormalities ◽  
High Density ◽  
Copy Number Alterations ◽  
Genome Wide Analysis ◽  
Conventional Cytogenetic Analysis ◽  
Genome Wide

Abstract Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic progenitors characterized by impaired blood cell production due to ineffective hematopoiesis and high propensity to acute myeloid leukemias. One of the prominent features of MDS is the high frequency of unbalanced chromosomal abnormalities that result in genetic imbalances and copy number alterations. Although the chromosomal segments involved in these abnormalities are thought to contain relevant genes to the pathogenesis of MDS, conventional analyses including FISH have failed to identify critical regions small enough to pinpoint their target genes. Affymetrix® GeneChip® 100K/500K mapping arrays were originally developed for large-scale genotyping of more than 100,000/500,000 SNPs in two separate arrays, but the quantitative nature of the preparative whole-genome amplification and array hybridization thereafter also allows for accurate copy number estimate of the genome using these platforms at the resolutions of 21.3 kb and 5.4 kb with 116,204 and 520,000 oligonucleotide probes, respectively. Here we developed robust algorithms (CNAG) for copy number detection using 100K and/or 500K arrays and analyzed 88 MDS samples on these platforms in order to identify relevant genes for development of MDS. With these huge numbers of uniformly distributed SNP probes, numerous copy number alterations were sensitively detected in cases with MDS with more numbers of abnormalities found in advanced diseases (RAEB and RAEB-t). In addition to large-scale alterations of various chromosomal segments previously reported in these syndromes, a number of small cryptic chromosomal abnormalities were identified that would escape conventional cytogenetic analysis or array CGH analysis. Minimum overlapping deletions in 5q, 7q, 12p, 13q, and 20q were precisely defined, although no pinpoint homozygous deletions were detected within these regions. A common 20q deletion spans a 400 kb segment harboring five transcriptomes and the common 12p deletion defines a 1.3 Mb region that contains the ETV6 gene. Other common overlapping abnormalities include deletions in 21q22, 17q13, and gains of 11q25. Genome-wide analysis of copy number changes using high-density oligonucleotide arrays provides valuable information about genetic abnormalities in MDS.

scholarly journals Molecular Network Approach Reveals Rictor as a Central Target of Cardiac ProtectomiRs

2021 ◽  
Vol 22 (17) ◽  
pp. 9539
Author(s):  
András Makkos ◽  
Bence Ágg ◽  
Zoltán V. Varga ◽  
Zoltán Giricz ◽  
Mariann Gyöngyösi ◽  
...  
Keyword(s):  
Drug Target ◽  
Drug Targets ◽  
Target Genes ◽  
Ischemic Postconditioning ◽  
Molecular Network ◽  
Pig Model ◽  
Node Degree ◽  
Central Target ◽  
Mrna Targets ◽  
Novel Drug

Cardioprotective medications are still unmet clinical needs. We have previously identified several cardioprotective microRNAs (termed ProtectomiRs), the mRNA targets of which may reveal new drug targets for cardioprotection. Here we aimed to identify key molecular targets of ProtectomiRs and confirm their association with cardioprotection in a translational pig model of acute myocardial infarction (AMI). By using a network theoretical approach, we identified 882 potential target genes of 18 previously identified protectomiRs. The Rictor gene was the most central and it was ranked first in the protectomiR-target mRNA molecular network with the highest node degree of 5. Therefore, Rictor and its targeting microRNAs were further validated in heart samples obtained from a translational pig model of AMI and cardioprotection induced by pre- or postconditioning. Three out of five Rictor-targeting pig homologue of rat ProtectomiRs showed significant upregulation in postconditioned but not in preconditioned pig hearts. Rictor was downregulated at the mRNA and protein level in ischemic postconditioning but not in ischemic preconditioning. This is the first demonstration that Rictor is the central molecular target of ProtectomiRs and that decreased Rictor expression may regulate ischemic postconditioning-, but not preconditioning-induced acute cardioprotection. We conclude that Rictor is a potential novel drug target for acute cardioprotection.

scholarly journals JQ1 affects BRD2-dependent and independent transcription regulation without disrupting H4-hyperacetylated chromatin states

2017 ◽  
Author(s):  
Lusy Handoko ◽  
Bogumil Kaczkowski ◽  
Chung-Chau Hon ◽  
Marina Lizio ◽  
Masatoshi Wakamori ◽  
...  
Keyword(s):  
Drug Targets ◽  
Target Genes ◽  
Nsclc Cell Line ◽  
Histone H4 ◽  
Transcription Start ◽  
Independent Manner ◽  
Downstream Target ◽  
Genome Wide ◽  
Integrative Analyses ◽  
Bet Protein

ABSTRACTThe bromodomain and extra-terminal domain (BET) proteins are promising drug targets for cancer and immune diseases. However, BET inhibition effects have been studied more in the context of bromodomain-containing protein 4 (BRD4) than BRD2, and the BET protein association to histone H4-hyperacetylated chromatin is not understood at the genome-wide level. Here, we report transcription start site (TSS)-resolution integrative analyses of ChIP-seq and transcriptome profiles in human non-small cell lung cancer (NSCLC) cell line H23. We show that di-acetylation at K5 and K8 of histone H4 (H4K5acK8ac) co-localizes with H3K27ac and BRD2 in the majority of active enhancers and promoters, where BRD2 has a stronger association with H4K5acK8ac than H3K27ac. Interestingly, although BET inhibition by JQ1 led to complete reduction of BRD2 binding to chromatin, only local changes of H4K5acK8ac levels were observed. In addition, a remarkable number of BRD2-bound genes, including MYC and its downstream target genes, were transcriptionally upregulated upon JQ1 treatment. Using BRD2-enriched sites and transcriptional activity analysis, we identified candidate transcription factors potentially involved in the JQ1 response in BRD2-dependent and independent manner.

Exploration of  the mechanism of Ziyin Tongluo Formula on preventing and treating postmenopausal osteoporosis based on the network pharmacology

2020 ◽  
Author(s):  
Rong-Bin Chen ◽  
Ying-Dong Yang ◽  
Kai Sun ◽  
Shan Liu ◽  
Wei Guo ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Postmenopausal Osteoporosis ◽  
Target Genes ◽  
Interaction Network ◽  
Network Pharmacology ◽  
Regulation Of Transcription ◽  
Active Ingredients ◽  
Active Components ◽  
Kegg Pathways ◽  
Key Genes

Abstract Background Postmenopausal osteoporosis (PMOP) is a global chronic and metabolic bone disease that poses huge challenges to individuals and society. Previous studies have confirmed that Ziyin Tongluo Formula (ZYTLF) has a good clinical effect in the treatment of PMOP. However, the material basis and mechanism of ZYLTF against PMOP has not been thoroughly explained. Methods TCMSP, TCMID, and BATMAN-TCM databases were used to identify the active ingredients and their putative targets. Genes associated with PMOP were mined from GeneCards, OMIM, DisGeNET databases, and then mapped with the putative targets to obtain overlapping target genes. A network model of "herb-active ingredient-overlapping target genes" was constructed and a protein-protein interaction network of overlapping target genes was built and the key genes were selected based on the MCC algorithm. The key genes were imported to the DAVID database to performs GO and KEGG pathway enrichment analyses. Results Ninety-two active components of ZYTLF corresponded to 243 targets, with 129 target genes interacting with PMOP, and 50 key genes were selected. GO analysis results showed that biological process mainly included positive regulation of transcription, negative regulation of apoptosis, and cell components were mainly nucleus, cytoplasm, and molecular functions mainly included enzyme binding, protein binding and transcription factor binding. There were two main types of significant KEGG pathways in PMOP, hormone-related signaling pathways (estrogen, prolactin, thyroid hormone) and inflammation-related pathways (TNF, PI3K-Akt, MAPK ). Conclusions The underlying therapeutic mechanisms of ZYTLF action on PMOP maybe is that, the active ingredients such as quercetin, kaempferol, luteolin act on ESR1, TNF, IL6, MAPK8 and other key genes, which mainly enrich in estrogen, TNF, PI3K-Akt, MAPK and other signaling pathways.

scholarly journals Genome-Wide Gene Expression Analysis Reveals a Dynamic Interplay between Luteotropic and Luteolytic Factors in the Regulation of Corpus Luteum Function in the Bonnet Monkey (Macaca radiata)

Endocrinology ◽  
2008 ◽  
Vol 150 (3) ◽  
pp. 1473-1484 ◽  
Author(s):  
S. Priyanka ◽  
P. Jayaram ◽  
R. Sridaran ◽  
R. Medhamurthy
Keyword(s):  
Gene Expression ◽  
Corpus Luteum ◽  
Signaling Pathways ◽  
Expression Analysis ◽  
Cross Talk ◽  
Early Pregnancy ◽  
Luteal Phase ◽  
Target Genes ◽  
Luteal Function ◽  
Genome Wide

Although LH is essential for survival and function of the corpus luteum (CL) in higher primates, luteolysis occurs during nonfertile cycles without a discernible decrease in circulating LH levels. Using genome-wide expression analysis, several experiments were performed to examine the processes of luteolysis and rescue of luteal function in monkeys. Induced luteolysis with GnRH receptor antagonist (Cetrorelix) resulted in differential regulation of 3949 genes, whereas replacement with exogenous LH (Cetrorelix plus LH) led to regulation of 4434 genes (1563 down-regulation and 2871 up-regulation). A model system for prostaglandin (PG) F2α-induced luteolysis in the monkey was standardized and demonstrated that PGF2α regulated expression of 2290 genes in the CL. Analysis of the LH-regulated luteal transcriptome revealed that 120 genes were regulated in an antagonistic fashion by PGF2α. Based on the microarray data, 25 genes were selected for validation by real-time RT-PCR analysis, and expression of these genes was also examined in the CL throughout the luteal phase and from monkeys treated with human chorionic gonadotropin (hCG) to mimic early pregnancy. The results indicated changes in expression of genes favorable to PGF2α action during the late to very late luteal phase, and expressions of many of these genes were regulated in an opposite manner by exogenous hCG treatment. Collectively, the findings suggest that curtailment of expression of downstream LH-target genes possibly through PGF2α action on the CL is among the mechanisms underlying cross talk between the luteotropic and luteolytic signaling pathways that result in the cessation of luteal function, but hCG is likely to abrogate the PGF2α-responsive gene expression changes resulting in luteal rescue crucial for the maintenance of early pregnancy. Results of genome-wide analyses suggest that curtailment of expression of LH target-genes through PGF2α action in corpus luteum involves cross talk between luteotropic and luteolytic signaling pathways.

A comprehensive review of online resources for microRNA–diseases associations: the state of the art

2021 ◽  
Author(s):  
Maryam Mahjoubin-Tehran ◽  
Samaneh Rezaei ◽  
Amin Jalili ◽  
Amirhossein Sahebkar ◽  
Seyed Hamid Aghaee-Bakhtiari
Keyword(s):  
Signaling Pathways ◽  
Target Genes ◽  
Therapy Response ◽  
Clinical Applications ◽  
Significant Development ◽  
Diagnosis And Prognosis ◽  
Mrna Targets ◽  
Disease Information ◽  
Therapeutic Tools ◽  
The Relationship

Abstract MicroRNAs (miRNAs) as small 19- to 24-nucleotide noncoding RNAs regulate several mRNA targets and signaling pathways. Therefore, miRNAs are considered key regulators in cellular pathways as well as various pathologies. There is substantial interest in the relationship between disease and miRNAs, which made that one of the important research topics. Interestingly, miRNAs emerged as an attractive approach for clinical application, not only as biomarkers for diagnosis and prognosis or in the prediction of therapy response but also as therapeutic tools. For these purposes, the identification of crucial miRNAs in disease is very important. Databases provided valuable experimental and computational miRNAs–disease information in an accessible and comprehensive manner, such as miRNA target genes, miRNA related in signaling pathways and miRNA involvement in various diseases. In this review, we summarized miRNAs–disease databases in two main categories based on the general or specific diseases. In these databases, researchers could search diseases to identify critical miRNAs and developed that for clinical applications. In another way, by searching particular miRNAs, they could recognize in which disease these miRNAs would be dysregulated. Despite the significant development that has been done in these databases, there are still some limitations, such as not being updated and not providing uniform and detailed information that should be resolved in future databases. This survey can be helpful as a comprehensive reference for choosing a suitable database by researchers and as a guideline for comparing the features and limitations of the database by developer or designer. Short abstract We summarized miRNAs–disease databases that researchers could search disease to identify critical miRNAs and developed that for clinical applications. This survey can help choose a suitable database for researchers.

scholarly journals VHLSynthetic Lethality Signatures Uncovered by Genotype-specific CRISPR-Cas9 Screens

2019 ◽  
Author(s):  
Ning Sun ◽  
Sakina Petiwala ◽  
Charles Lu ◽  
Jessica E Hutti ◽  
Min Hu ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cancer Cells ◽  
Drug Targets ◽  
Target Genes ◽  
Synthetic Lethality ◽  
Suppressor Gene ◽  
Cell Renal Cell Carcinoma ◽  
Von Hippel Lindau ◽  
Genome Wide ◽  
Tumor Suppressor Gene Inactivation

AbstractBackgroundGenome-wide CRISPR-Cas9 essentiality screening represents a powerful approach to identify genetic vulnerabilities in cancer cells. Here, we applied this technology and designed a strategy to identify target genes that are synthetic lethal (SL) withvon Hippel-Lindau(VHL) tumor suppressor gene. Inactivation ofVHLhas been frequently found in clear cell renal cell carcinoma (ccRCC). Its SL partners serve as potential drug targets for the development of targeted cancer therapies.ResultsWe performed parallel genome-wide CRISPR screens in two pairs of isogenic ccRCC cell lines that differ only in theVHLstatus. Comparative analyses of screening results not only confirmed a well-known role for mTOR signaling in renal carcinoma, but also identified DNA damage response and selenocysteine biosynthesis pathways as major SL targets inVHL-inactivated cancer cells. Follow-up studies provided cellular and mechanistic insights into SL interactions of these pathway genes with theVHLgene.ConclusionsUsing isogenic CRISPR screening approach, we uncovered novel biological processes that are SL withVHL, which can be exploited for drug development for ccRCC. Our CRISPR and RNA-seq datasets provide a rich resource for future investigation of the function of the VHL tumor suppressor protein. Our work demonstrates the efficiency of CRISPR-based synthetic lethality screening in human isogenic cell pairs. Similar strategies could be employed to unveil SL partners with other oncogenic drivers.

scholarly journals GWAS defines pathogenic signaling pathways and prioritizes drug targets for IgA nephropathy

2021 ◽  
Author(s):  
Krzysztof Kiryluk ◽  
Elena Sanchez-Rodriguez ◽  
Xu-jie Zhou ◽  
Francesca Zanoni ◽  
Lili Liu ◽  
...  
Keyword(s):  
Association Study ◽  
Signaling Pathways ◽  
Iga Nephropathy ◽  
Drug Targets ◽  
Disease Onset ◽  
Regulatory Elements ◽  
Total Serum ◽  
Genome Wide ◽  
Serum Iga ◽  
A Genome

IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. We performed a genome-wide association study involving 10,146 kidney biopsy-diagnosed IgAN cases and 28,751 matched controls across 17 international cohorts. We defined 30 independent genome-wide significant risk loci jointly explaining 11% of disease risk. A total of 16 loci were novel, including TNFSF4, REL, CD28, CXCL8/PF4V1, LY86, LYN, ANXA3, TNFSF8/15, REEP3, ZMIZ1, RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The SNP-based heritability of IgAN was estimated at 23%. We observed a positive genetic correlation between IgAN and total serum IgA levels, allergy, tonsillectomy, and several infections, and a negative correlation with inflammatory bowel disease. All significant non-HLA loci shared with serum IgA levels had a concordant effect on the risk of IgAN. Moreover, IgAN loci were globally enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. The explained heritability was enriched in the regulatory elements of cells from the immune and hematopoietic systems and intestinal mucosa, providing support for the pathogenic role of extra-renal tissues. The polygenic risk of IgAN was associated with early disease onset, increased lifetime risk of kidney failure, as well as hematuria and several other traits in a phenome-wide association study of 590,515 individuals. In the comprehensive functional annotation analysis of candidate causal genes across genome-wide significant loci, we observed the convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.

scholarly journals Functional Dependency Analysis Identifies Potential Druggable Targets in Acute Myeloid Leukemia

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3710
Author(s):  
Yujia Zhou ◽  
Gregory P. Takacs ◽  
Jatinder K. Lamba ◽  
Christopher Vulpe ◽  
Christopher R. Cogle
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Drug Targets ◽  
Gene Knockout ◽  
Three Dimensional ◽  
Term Survival ◽  
Genome Wide ◽  
Druggable Targets ◽  
Acute Myeloid

Refractory disease is a major challenge in treating patients with acute myeloid leukemia (AML). Whereas the armamentarium has expanded in the past few years for treating AML, long-term survival outcomes have yet to be proven. To further expand the arsenal for treating AML, we searched for druggable gene targets in AML by analyzing screening data from a lentiviral-based genome-wide pooled CRISPR-Cas9 library and gene knockout (KO) dependency scores in 15 AML cell lines (HEL, MV411, OCIAML2, THP1, NOMO1, EOL1, KASUMI1, NB4, OCIAML3, MOLM13, TF1, U937, F36P, AML193, P31FUJ). Ninety-four gene KOs met the criteria of (A) specifically essential to AML cell survival, (B) non-essential in non-AML cells, and (C) druggable according to three-dimensional (3D) modeling or ligand-based druggability scoring. Forty-four of 94 gene-KOs (47%) had an already-approved drug match and comprised a drug development list termed “deKO.” Fifty of 94 gene-KOs (53%) had no drug in development and comprised a drug discovery list termed “disKO.” STRING analysis and gene ontology categorization of the disKO targets preferentially cluster in the metabolic processes of UMP biosynthesis, IMP biosynthesis, dihydrofolate metabolism, pyrimidine nucleobase biosynthesis, vitellogenesis, and regulation of T cell differentiation and hematopoiesis. Results from this study serve as a testable compendium of AML drug targets that, after validation, may be translated into new therapeutics.

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