Exploration of retinoblastoma pathogenesis with bioinformatics
Ontology highlight
ABSTRACT: Background
Differentially expressed genes (DEGs) from retinoblastoma (RB) tissues play key roles in the progression of RB. However, the role of DEGs in different subtypes and stages of RB has not yet been systematically analyzed. Methods
In this study, the DEGs for tumor and adjacent from 3 RB data sets GSE24673, GSE97508, and GSE110811 were analyzed with regard to the different subtypes and stages of the disease. Results
Through comparison with adjacent tissues, a total of 78 upregulated genes and 155 downregulated genes from the RB tissues were identified across the 3 data sets. Gene set enrichment analysis (GSEA) showed that the 3 representative genes CDK1, CDC20, and BUB1, which were all upregulated, could promote the cell cycle in RB. Compared with adjacent tissues in GSE97508, a total of 19 gigantol-targeted genes were predicted to be upregulated in invasive RB tissues. On the other hand, DEGs for tumor and adjacent from 3 RB data sets GSE24673, GSE97508, and GSE110811 were integrated with regard to invasiveness and stages of the disease, and another 19 DEGs were subsequently identified. Among these genes, UHRF1 was the only identified upregulated gene, while the other 18 were all downregulated genes. Cell Counting Kit-8 (CCK-8) experiment and GSEA results showed that UHRF1 can promote the proliferation and invasion of RB. Conversely, the downregulated representative gene CADM1 is a tumor suppressor gene, which can inhibit the progression of RB. Conclusions
This study indicated that the verified DEGs are continuously and consistently expressed in different subtypes and stages of RB. These DEGs may be the key to understanding the development and invasion of RB.
SUBMITTER: Zhang Y
PROVIDER: S-EPMC8797805 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:IntroductionRetinoblastoma (RB) is one common pediatric malignant tumor with dismal outcomes. Heterogeneity of RB and subtypes of RB were identified but the association between the subtypes of RB and RB progression have not been fully investigated.MethodsFour public datasets were downloaded from Gene expression omnibus and normalization was performed to remove batch effect. Two public datasets were explored to obtain the RB progression gene signatures by differentially expression analysis while another two datasets were iterated for RB subtypes identification using consensus clustering. After the RB progressive subtype gene signatures were identified, we tested the diagnostic capacity of these gene signatures by receiver operation curve.ResultsThree hundreds and forty six genes that were enriched in cell cycle were identified as the progression signature in RB from two independent datasets. Four subtypes of RB were stratified by consensus clustering. A total of 21 genes from RB progression signature were differentially expressed between RB subtypes. One subtype with low expression cell division genes have less progression of all four subtypes. A panel of five RB subtype genes (CLUL1, CNGB1, ROM1, LRRC39 and RDH12) predict progression of RB.ConclusionRetinoblastoma is a highly heterogeneous tumor and the level of cell cycle related gene expression is associated with RB progression. A subpopulation of RB with high expression of visual perception has less progressive features. LRRC39 is potentially the RB progression subtype biomarker.
| S-EPMC7246025 | biostudies-literature
Project description:BackgroundRetinoblastoma (RB) is the most common prevalent intraocular malignancy among infants and children, particularly in underdeveloped countries. With advancements in genomics and transcriptomics, noncoding RNAs have been increasingly utilized to investigate the molecular pathology of diverse diseases.AimsThis study aims to establish the competing endogenous RNAs network associated with RB, analyse the function of mRNAs and lncRNAs, and finds the relevant regulatory network.Methods and resultsThis study establishes a network of competing endogenous RNAs by Spearman correlation analysis and prediction based on RB patients and healthy children. Enrichment analyzes based on Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes are conducted to analyze the potential biological functions of lncRNA and mRNA networks. Weighted gene co-expression network analysis (WGCNA) is employed to identify gene cluster modules exhibiting the strongest correlation with RB. The results indicate a significant correlation between the lncRNA MIR17HG (R = .73, p = .02) and the RB phenotype. ceRNA networks reveal downstream miRNAs (hsa-mir-425-5p and hsa-mir455-5p) and mRNAs (MDM2, IPO11, and ITGA1) associated with MIR17Hg. As an inhibitor of the p53 signaling pathway, MDM2 can suppress the development of RB.ConclusionIn conclusion, lncRNAs play a role in RB, and the MIR17HG/hsa-mir-425-5p/MDM2 pathway may contribute to RB development by inhibiting the p53 signaling pathway.
| S-EPMC10864729 | biostudies-literature
Project description:BackgroundAlopecia areata (AA) describes a sudden localized patchy alopecia. The cause of AA is not completely clear and its incidence may be related to genetic, autoimmune, and environmental factors.AimTo explore the possible mechanisms of AA and to provide a basis for the early diagnosis and treatment of AA.MethodsGene microarray data from 122 scalp skin biopsy tissue samples from patients with AA or healthy controls from the Gene-Cloud of Biotechnology Information database were analyzed using bioinformatics analysis methods. Molecular network analysis of the differentially expressed genes (DEGs) was conducted by Cytocluster using the Molecular Complex Detection (MCODE) algorithm.ResultsThe gene expression profile of skin lesions from patients with AA was significantly altered, with 111 DEGs found in the skin lesions of AA, compared with that of the healthy skin. The DEGs were mainly related to biological processes such as the development of the epidermis and inflammatory reaction. The protein-protein interaction network analysis of DEGs revealed bone morphogenetic protein 2 (BMP2) as a core protein interaction network. BMP2 acted not only via the inflammatory response but also via the signaling pathways in epithelial cell development and epidermal cell differentiation to affect the epidermal development. MCODE analysis further showed that keratins (KRTs) and keratin-associated proteins (KRTAPs) can affect the epidermal development via the epidermal development pathway.ConclusionsThe abnormal development of the epidermis and inflammatory reactions in skin tissue play important roles in the pathogenesis of AA and are closely related to BMP2, KRTs, and KRTAPs genes.LimitationsOur study was limited by experimental verification.
| S-EPMC6340232 | biostudies-literature
Project description:BackgroundThis article aims to explore whether ursolic acid (UA) inhibits the progression of retinoblastoma (Rb) by regulating stearoyl-CoA desaturase (SCD).MethodsThe Gene Expression Omnibus (GEO) database was used to filter the chip, then the GEO2R software was used to analyze the microarray data (GSE97508, GSE24673, and GSE110811). Gene set enrichment analysis (GSEA) was used to analyze the relationship between the expression level of SCD and the proliferation, migration, invasion, and inflammation in Rb patients. SO-RB50 and Y79 cell proliferation, migration, and invasion were assessed by the CCK-8 assay, the colony formation assay, the Transwell assay, and the wound scratch test. The protein expression levels of SCD were measured by western blot. The mRNA expression levels of IL-8, IL-6, CXCL1, and CCL2 were measured by RT-qPCR. The protein expression levels of IL-8 and IL-6 were measured by ELISA. A xenograft nude mouse model was established to evaluate the effect of UA on tumor growth in male BALB/c mice.ResultsThe expression levels of SCD were related to cell proliferation, migration, invasion, and inflammation. UA inhibited SO-RB50 and Y79 cell proliferation, migration, and invasion. At the same time, UA suppressed tumor growth in the xenograft nude mouse model. Overexpression of SCD promoted SO-RB50 and Y79 cell proliferation, migration, invasion, and inflammation, while SCD knockout inhibited SO-RB50 and Y79 cell proliferation, migration, invasion, and inflammation. Importantly, UA inhibited the proliferation, migration, and invasion of Rb cells through SCD inhibition.ConclusionsUA inhibited the proliferation, migration, and invasion of Rb cells through SCD. This provides a new scientific basis for targeted therapy of Rb.
| S-EPMC8576664 | biostudies-literature
Project description:BackgroundNo in-depth systematic evidence is available for assessing retinoblastoma malignancy and eligibility for subsequent treatment.MethodsThe Cochrane Library, EMBASE, PubMed, Web of Science, and China Biology Medicine databases were searched, and 16 studies comprising 718 retinoblastoma patients were included. Pooled odds ratios (ORs) and summary correlation coefficients (r) with 95% confidence intervals (CIs) in random-effects, fixed-effects or quality-effects models were calculated using Review Manager 5.3 and MetaXL. GO functional annotation and KEGG pathway analysis were performed using the GO and STRING databases.ResultsWe observed significant associations between high levels of MMP-1 (OR, 4.21; 95% CI 1.86-9.54), MMP-2 (OR, 11.18; 95% CI 4.26-29.30), MMP-9 (OR, 10.41, 95% CI 4.26-25.47), and VEGF (OR, 8.09; 95% CI 4.03-16.20) with tumor invasion; high levels of MMP-1 (OR, 3.58; 95% CI 1.48-8.71), MMP-2 (OR, 2.96; 95% CI 1.32-6.64), MMP-9 (OR, 5.49; 95% CI 3.55-8.48) and VEGF (OR, 5.30; 95% CI 2.93-9.60) with poor differentiation; and overexpression of MMP-9 (OR, 5.17; 95% CI 2.85-9.38) with advanced clinical stages. Moreover, MMP-9 and VEGF expression were positively correlated (r, 0.61; 95% CI 0.38-0.77). Multiple GO terms were enriched associated with MMP-1, MMP-2, MMP-9 and VEGF, and they are closely associated with pathways, proteoglycans and microRNAs related to cancer.ConclusionsMMP-1, MMP-2, MMP-9 and VEGF play important roles in the development and progression of retinoblastoma. High levels of MMP-1, MMP-2, MMP-9 and VEGF are credible implications for increased malignancy, thus the need for more aggressive treatments.
| S-EPMC6636009 | biostudies-literature
Project description:PURPOSE:Retinoblastoma (RB), a primary pediatric intraocular tumor, arises from primitive retinal layers. Several novel molecular strategies are being developed for the clinical management of RB. miRNAs are known to regulate cancer-relevant biological processes. Here, the role of selected miRNAs, namely, miR-532-5p and miR-486-3p, has been analyzed for potential therapeutic targeting in RB. METHODS:A comprehensive bioinformatic analysis was performed to predict the posttranscriptional regulators (miRNAs) of the select panel of genes [Group 1: oncogenes (HMGA2, MYCN, SYK, FASN); Group 2: cancer stem cell markers (TACSTD, ABCG2, CD133, CD44, CD24) and Group 3: cell cycle regulatory proteins (p53, MDM2)] using Microcosm, DIANALAB, miRBase v 18, and REFSEQ database, and RNA hybrid. The expressions of five miRNAs, namely, miR-146b-5p, miR-532-5p, miR-142-5p, miR-328, and miR-486-3p, were analyzed by qRT-PCR on primary RB tumor samples (n = 30; including 17 invasive RB tumors and 13 noninvasive RB tumors). Detailed complementary alignment between 5' seed sequence of differentially expressed miRNAs and the sequence of target genes was determined. Based on minimum energy level and piCTAR scores, the gene targets were selected. Functional roles of these miRNA clusters were studied by using mimics in cultured RB (Y79, Weri Rb-1) cells in vitro. The gene targets (SYK and FASN) of the studied miRNAs were confirmed by qRT-PCR and western blot analysis. Cell proliferation and apoptotic studies were performed. RESULTS:Nearly 1948 miRNAs were identified in the in silico analysis, From this list, only 9 upregulated miRNAs (miR-146b-5p, miR-305, miR-663b, miR-299, miR-532-5p, miR-892b, miR-501, miR-142-5p, and miR-513b) and 10 downregulated miRNAs (miR-1254, miR-328, miR-133a, miR-1287, miR-1299, miR-375, miR-486-3p, miR-720, miR-98, and miR-122*) were found to be common with the RB serum miRNA profile. Downregulation of five miRNAs (miR-146b-5p, miR-532-5p, miR-142-5p, miR-328, and miR-486-3p) was confirmed experimentally. Predicted common oncogene targets (SYK and FASN) of miR-486-3p and miR-532-5p were evaluated for their mRNA and protein expression in these miRNA mimic-treated RB cells. Experimental overexpression of these miRNAs mediated apoptotic cell death without significantly altering the cell cycle in RB cells. CONCLUSION:Key miRNAs in RB pathogenesis were identified by an in silico approach. Downregulation of miR-486-3p and miR-532-5p in primary retinoblastoma tissues implicates their role in tumorigenesis. Prognostic and therapeutic potential of these miRNA was established by the miRNA mimic strategy.
| S-EPMC4429751 | biostudies-literature
Project description:Streptococcus pneumoniae is an opportunistic human pathogen that causes invasive diseases, including pneumonia, with greater health risks upon influenza A virus (IAV) co-infection. To facilitate pathogenesis studies in vivo, we developed an inducible CRISPR interference system that enables genome-wide fitness testing in one sequencing step (CRISPRi-seq). We applied CRISPRi-seq to assess bottlenecks and identify pneumococcal genes important in a murine pneumonia model. A critical bottleneck occurs at 48 h with few bacteria causing systemic infection. This bottleneck is not present during IAV superinfection, facilitating identification of pneumococcal pathogenesis-related genes. Top in vivo essential genes included purA, encoding adenylsuccinate synthetase, and the cps operon required for capsule production. Surprisingly, CRISPRi-seq indicated no fitness-related role for pneumolysin during superinfection. Interestingly, although metK (encoding S-adenosylmethionine synthetase) was essential in vitro, it was dispensable in vivo. This highlights advantages of CRISPRi-seq over transposon-based genetic screens, as all genes, including essential genes, can be tested for pathogenesis potential.
| S-EPMC7855995 | biostudies-literature
Project description:BackgroundHIV-associated encephalitis (HIVE) is one of the common complications of HIV infection, and the pathogenesis of HIVE remains unclear, while lncRNA might be involved it. In this study, we made re-annotation on the expression profiling from the HIVE study in the public database, identified the lncRNA that might be involved in HIVE, and explored the possible mechanism.MethodsIn the GEO public database, the microarray expression profile (GSE35864) of three regions of brain tissues (white matter, frontal cortex and basal ganglia brain tissues) was chosen, updated annotation was performed to construct the non-cording-RNA (ncRNA) microarray data. Morpheus was used to identify the differential expressed ncRNA, and Genbank of NCBI was used to identify lncRNAs. The StarBase, PITA and miRDB databases were used to predict the target miRNAs of lncRNA. The TargetScan, PicTar and MiRanda databases were used to predict the target genes of miRNAs. The GO and KEGG pathway analysis were used to make function analysis on the targets genes.ResultsSeventeen differentially expressed lncRNAs were observed in the white matter of brain tissues, for which 352 target miRNAs and 6,659 target genes were predicted. The GO function analysis indicated that the lncRNAs were mainly involved in the nuclear transcription and translation processes. The KEGG pathway analysis showed that the target genes were significantly enriched in 33 signal pathways, of which 11 were clearly related to the nervous system function.DiscussionThe brand-new and different microarray results can be obtained through the updated annotation of the chips, and it is feasible to identify lncRNAs from ordinary chips. The results suggest that lncRNA may be involved in the occurrence and development of HIVE, which provides a new direction for further research on the diagnosis and treatment of HIVE.
| S-EPMC6187992 | biostudies-literature
Project description:PurposeRetinoblastoma (RB) sets the paradigm for hereditary cancer syndromes, for which medical care can change depending on the results of genetic testing. In this study, we screened constitutional mutations in the RB1 gene via a method combining DNA sequencing and multiplex ligation-dependent probe amplification (MLPA), and performed a preliminary exploration of genotype-phenotype correlations.MethodsThe peripheral blood of 85 retinoblastoma probands, including 39 bilateral and 46 unilateral, was collected, and genomic DNA was extracted. DNA sequencing was conducted first. MLPA analysis was applied for patients with bilateral RB with negative sequencing results and unilateral probands whose age at diagnosis was less than 1 year old.ResultsThirty-four distinct mutations were identified in 40 (47.1%) of the 85 probands (36 bilateral and four unilateral), of which 20% (8/40) was identified by MLPA. The total detection rate in bilateral cases was 92.3% (36/39). Of the total mutations identified, 77.5% (31/40) probands with a mean age of 10.7 months at diagnosis had null mutations, and 22.5% (9/40) with a mean age of 13.5 months at diagnosis had in-frame mutations. Of the 31 probands with null mutations, bilateral RB accounted for 96.8% (30/31). Of the nine probands with in-frame mutations, 66.7% had bilateral RB. There were seven new mutations of RB1 identified in this report, including six null mutations and one missense mutation. Clinical staging of the tumor did not show obvious differences between patients with null mutations and in-frame mutations.ConclusionsOur results confirm that the type of mutation is related to age of onset and the laterality, but not staging of the retinoblastoma tumor. MLPA is a reliable method for detecting gross deletion or duplication of the RB1 gene. The combination of sequencing and MLPA improves the clinical diagnosis of RB.
| S-EPMC4000713 | biostudies-literature
Project description:Retinoblastoma (RB) is the commonest malignant tumor of the infant retina. Besides genetic changes, epigenetic events are also considered to implicate the occurrence of RB. This study aimed to identify significantly altered protein-coding genes, DNA methylation, microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and their molecular functions and pathways associated with RB, and investigate the epigenetically regulatory mechanism of DNA methylation modification and non-coding RNAs on key genes of RB via bioinformatics method.We obtained multi-omics data on protein-coding genes, DNA methylation, miRNAs, and lncRNAs from the Gene Expression Omnibus database. We identified differentially expressed genes (DEGs) using the Limma package in R, discerned their biological functions and pathways using enrichment analysis, and conducted the modular analysis based on protein-protein interaction network to identify hub genes of RB. Survival analyses based on The Cancer Genome Atlas clinical database were performed to analyze prognostic values of key genes of RB. Subsequently, we identified the differentially methylated genes, differentially expressed miRNAs (DEMs) and lncRNAs (DELs), and intersected them with key genes to analyze possible targets of the underlying epigenetic regulatory mechanisms. Finally, the ceRNA network of lncRNAs-miRNAs-mRNAs was constructed using Cytoscape.A total of 193 DEGs, 74 differentially methylated-DEGs (DM-DEGs), 45 DEMs, 5 DELs were identified. The molecular pathways of DEGs were enriched in cell cycle, p53 signaling pathway, and DNA replication. A total of 10 key genes were identified and found significantly associated with poor survival outcome based on survival analyses, including CDK1, BUB1, CCNB2, TOP2A, CCNB1, RRM2, KIF11, KIF20A, NDC80, and TTK. We further found that hub genes MCM6 and KIF14 were differentially methylated, key gene RRM2 was targeted by DEMs, and key genes TTK, RRM2, and CDK1 were indirectly regulated by DELs. Additionally, the ceRNA network with 222 regulatory associations was constructed to visualize the correlations between lncRNAs-miRNAs-mRNAs.This study presents an integrated bioinformatics analysis of genetic and epigenetic changes that may be associated with the development of RB. Findings may yield many new insights into the molecular biomarker candidates and epigenetically regulatory targets of RB.
| S-EPMC7676602 | biostudies-literature