Isolation and bioinformatics analysis of differentially methylated genomic fragments in human gastric cancer.
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ABSTRACT:
SUBMITTER: Liao AJ
PROVIDER: S-EPMC2693678 | biostudies-literature | 2008 Mar
REPOSITORIES: biostudies-literature
Publications
Isolation and bioinformatics analysis of differentially methylated genomic fragments in human gastric cancer.
Liao Ai-Jun AJ Su Qi Q Wang Xun X Zeng Bin B Shi Wei W
World journal of gastroenterology 20080301 9
<h4>Aim</h4>To isolate and analyze the DNA sequences which are methylated differentially between gastric cancer and normal gastric mucosa.<h4>Methods</h4>The differentially methylated DNA sequences between gastric cancer and normal gastric mucosa were isolated by methylation-sensitive representational difference analysis (MS-RDA). Similarities between the separated fragments and the human genomic DNA were analyzed with Basic Local Alignment Search Tool (BLAST).<h4>Results</h4>Three differentiall ...[more]
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Project description:Methylation functions in the pathogenesis of cervical cancer. In the present study, we applied an integrated bioinformatics analysis to identify the aberrantly methylated and differentially expressed genes (DEGS), and their related pathways in cervical cancer. Data of gene expression microarrays (GSE9750) and gene methylation microarrays (GSE46306) were gained from Gene Expression Omnibus (GEO) databases. Hub genes were identified by 'limma' packages and Venn diagram tool. Functional analysis was conducted by FunRich. Search Tool for the Retrieval of Interacting Genes Database (STRING) was used to analyze protein-protein interaction (PPI) information. Gene Expression Profiling Interactive Analysis (GEPIA), immunohistochemistry staining, and ROC curve analysis were conducted for validation. Gene Set Enrichment Analysis (GSEA) was also performed to identify potential functions.We retrieved two upregulated-hypomethylated oncogenes and eight downregulated-hypermethylated tumor suppressor genes (TSGs) for functional analysis. Hypomethylated and highly expressed genes (Hypo-HGs) were significantly enriched in cell cycle and autophagy, and hypermethylated and lowly expressed genes (Hyper-LGs) in estrogen receptor pathway and Wnt/β-catenin signaling pathway. Estrogen receptor 1 (ESR1), Erythrocyte membrane protein band 4.1 like 3 (EPB41L3), Endothelin receptor B (EDNRB), Inhibitor of DNA binding 4 (ID4) and placenta-specific 8 (PLAC8) were hub genes. Kaplan-Meier method was used to evaluate survival data of each identified gene. Lower expression levels of ESR1 and EPB41L3 were correlated with a shorter survival time. GSEA results showed that 'cell adhesion molecules' was the most enriched item. This research inferred the candidate genes and pathways that might be used in the diagnosis, treatment, and prognosis of cervical cancer.
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Project description:Pancreatic cancer remains one of the chief contributors to cancer related deaths on a global scale, with its diagnosis often associated with poor prognosis and high mortality. Accumulating literature continues to highlight the role of aberrant DNA methylation in relation to pancreatic cancer progression. Integrated bioinformatics approaches in the characterization of methylated-differentially expressed genes (MeDEGs) in pancreatic cancer were employed to enhance our understanding of the potential underlying molecular mechanisms of this cancer. We initially identified differentially expressed genes (DEGs) between 178 pancreatic cancer samples and 4 normal samples and differentially methylated genes (DMGs) based on 185 pancreatic cancer samples as well as 10 normal samples by analyzing RNA sequencing data in the TCGA database. Eventually, 31 MeDEGs including 5 hypomethylated/upregulated genes and 26 hypermethylated/downregulated genes were identified. Univariate Cox model and Kaplan-Meier method revealed that, among 31 MeDEGs, 5 hypermethylated/downregulated genes (ZNF804A, ZFP82, TRIM58, SOX17, and C12orf42) were correlated with poor survival of patients with pancreatic cancer. KEGG pathway enrichment analysis by GSEA 3.0 and the protein-protein interaction (PPI) network revealed that these 5 MeDEGs were enriched in numerous cancer-related pathways in addition to interacting with each other, highlighting a significant role in the development of pancreatic cancer. Taken together, the key findings of the current study demonstrate that ZNF804A, ZFP82, TRIM58, SOX17, and C12orf42 are hypermethylated/downregulated genes in pancreatic cancer and may be associated, through their modulation of specific pathways, with unfavorable pancreatic cancer prognosis.
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Project description:Current literature suggests that epigenetically regulated super-enhancers (SEs) are drivers of aberrant gene expression in cancers. Many tumor types are still missing chromatin data to define cancer-specific SEs and their role in carcinogenesis. In this work, we develop a simple pipeline, which can utilize chromatin data from etiologically similar tumors to discover tissue-specific SEs and their target genes using gene expression and DNA methylation data. As an example, we applied our pipeline to human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV?+?OPSCC). This tumor type is characterized by abundant gene expression changes, which cannot be explained by genetic alterations alone. Chromatin data are still limited for this disease, so we used 3627 SE elements from public domain data for closely related tissues, including normal and tumor lung, and cervical cancer cell lines. We integrated the available DNA methylation and gene expression data for HPV?+?OPSCC samples to filter the candidate SEs to identify functional SEs and their affected targets, which are essential for cancer development. Overall, we found 159 differentially methylated SEs, including 87 SEs that actively regulate expression of 150 nearby genes (211 SE-gene pairs) in HPV?+?OPSCC. Of these, 132 SE-gene pairs were validated in a related TCGA cohort. Pathway analysis revealed that the SE-regulated genes were associated with pathways known to regulate nasopharyngeal, breast, melanoma, and bladder carcinogenesis and are regulated by the epigenetic landscape in those cancers. Thus, we propose that gene expression in HPV?+?OPSCC may be controlled by epigenetic alterations in SE elements, which are common between related tissues. Our pipeline can utilize a diversity of data inputs and can be further adapted to SE analysis of diseased and non-diseased tissues from different organisms.
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Project description:GRP78 is a molecular chaperone located in endoplasmic reticulum, and induces folding and assembly of newly-synthesized proteins, proteasome degradation of aberrant proteins, and translocation of secretory proteins, autophagy, and epithelial-mesenchymal transition. We performed a systematic meta- and bioinformatics analysis through multiple online databases up to March 14, 2017. It was found that up-regulated GRP78 expression in gastric cancer, compared with normal mucosa at both protein and mRNA levels (p < 0.05). GRP78 expression was positively correlated with depth of invasion, TNM staging and dedifferentiation of gastric cancer (p < 0.05), while its mRNA expression was negatively correlated with depth of invasion, histological grading and dedifferentiation (p < 0.05). A positive association between GRP78 expression and unfavorable overall survival was found in patients with gastric cancer (p < 0.005). A higher GRP78 mRNA expression was positively correlated with overall and progression-free survival rates of all cancer patients, even stratified by aggressive parameters, or as an independent factor (p < 0.05). These findings indicated that GRP78 expression might be employed as a potential marker to indicate gastric carcinogenesis and subsequent progression, even prognosis.
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Project description:BackgroundMethylation plays a key role in the aetiology and pathogenesis of prostate cancer (PCa). This study aimed to identify aberrantly methylated differentially expressed genes (DEGs) and pathways in PCa and explore the underlying mechanisms of tumourigenesis.MethodsExpression profile (GSE29079) and methylation profile (GSE76938) datasets were obtained from the Gene Expression Omnibus (GEO). We used R 3.4.4 software to assess aberrantly methylated DEGs. The Cancer Genome Atlas (TCGA) RNA sequencing and Illumina HumanMethylation450 DNA methylation data were utilized to validate screened genes. Functional enrichment analysis of the screened genes was performed, and a protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Gens (STRING). The results were visualized in Cytoscape. After confirmation using TCGA, cBioPortal was used to examine alterations in genes of interest. Then, protein localization in PCa cells was observed using immunohistochemistry.ResultsOverall, 536 hypomethylated upregulated genes were identified that were enriched in biological processes such as negative regulation of transcription, osteoblast differentiation, intracellular signal transduction, and the Wnt signalling pathway. Pathway enrichment showed significant changes in factors involved in AMPK signalling, cancer, and adherens junction pathways. The hub oncogenes were AKT1, PRDM10, and FASN. Additionally, 322 hypermethylated downregulated genes were identified that demonstrated enrichment in biological processes including positive regulation of the MAPK cascade, muscle contraction, ageing, and signal transduction. Pathway analysis indicated enrichment in arrhythmogenic right ventricular cardiomyopathy (ARVC), focal adhesion, dilated cardiomyopathy, and PI3K-AKT signalling. The hub tumour suppressor gene was FLNA. Immunohistochemistry showed that AKT1, FASN, and FLNA were mainly expressed in PCa cell cytoplasm, while PRDM10 was mainly expressed in nuclei.ConclusionsOur results identify numerous novel genetic and epigenetic regulatory networks and offer molecular evidence crucial to understanding the pathogenesis of PCa. Aberrantly methylated hub genes, including AKT1, PRDM10, FASN, and FLNA, can be used as biomarkers for accurate PCa diagnosis and treatment. In conclusion, our study suggests that AKT1, PRDM10, and FASN may be tumour promoters and that FLNA may be a tumour suppressor in PCa. We hope these findings will draw more attention to these hub genes in future cancer studies.
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