Network of Microrna, Transcription Factors, Target Genes and Host Genes in Human Mesothelioma

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Network of Microrna, Transcription Factors, Target Genes and Host Genes in Human Mesothelioma EXPERIMENTAL AND THERAPEUTIC MEDICINE 13: 3039-3046, 2017 Network of microRNA, transcription factors, target genes and host genes in human mesothelioma GUANHUA ZHANG1,2, ZHIWEN XU1-3 and NING WANG2,3 1Department of Software Engineering; 2Key Laboratory of Symbol Computation and Knowledge Engineering of the Ministry of Education; 3Department of Computer Science and Technology, Jilin University, Changchun, Jilin 130012, P.R. China Received April 21, 2015; Accepted May 16, 2016 DOI: 10.3892/etm.2017.4296 Abstract. Significant progress has been made into the elucida- a reference to aid further elucidation of the pathogenesis of tion of the etiology of mesothelioma at the level of the genes mesothelioma. and miRNA. Nevertheless, researchers in this field remain unable to systematically construct a network that demon- Introduction strates the specific relationships between genes, miRNA and transcription factors (TFs). TFs are key regulatory elements Mesothelioma is a rare type of human cancer which arises in that control gene expression. In the present study, according to mesothelial cells covering certain parts of the body. The most the transcriptional regulatory rule, three regulatory networks common anatomical site for mesothelioma is the pleura, which were constructed using experimentally validated elements to forms the outer lining of the lungs and internal chest wall. explore the pathogenesis of mesothelioma. We focused on Mesothelioma can also develop in the peritoneum, which is the the regulatory relationship between the miRNA and its host lining of the abdominal cavity, the pericardium or the tunica gene, the miRNA and its target gene, and the miRNA and TFs. vaginalis (1). The majority of individuals who have worked Expressed, related and global networks were constructed, and as miners suffer from mesothelioma, as they have inhaled or the similarities and differences between them were analyzed. ingested asbestos fibers and live with the danger of exposure Notably, the differentially expressed network used in the to airborne asbestos dust and fibers (2). present study, which was based on experimentally validated Previous experimentation has demonstrated that differen- data, contained numerous incorrect expression signal path- tially expressed genes (DEGs) and miRNA have an effect on ways for the pathogenesis of mesothelioma. In theory, if these the development, metastasis and therapy of mesothelioma (3). errors are corrected, this cancer may be prevented or cured. Although the DEGs and miRNA associated with mesothelioma Subsequent analysis of the differentially expressed nodes have been elucidated, a detailed mechanism of the transcrip- and pathways may help to explain the pathogenesis of meso- tional regulation of mesothelioma is yet to be clarified (4). thelioma. Notably, some of these exhibited a self‑adaption Furthermore, the related genes and miRNA of mesothelioma relationship, which was detected by listing the upstream and have fewer roles than the differentially expressed factors (5). downstream elements in a table with differentially expressed Transcription factors (TFs) and miRNA are prominent genes and miRNA. The findings of the present study demon- regulators of gene expression (6). TFs are proteins that bind strated detailed transcriptional regulation, which may serve as to a specific DNA sequence to regulate gene expression. They function as activators or repressors alone or in cooperation, which results in the upregulation or downregulation of the transcription of neighboring genes (1). miRNA are small non‑coding RNA molecules that also regulate gene expression at the post‑transcriptional level; therefore, they have funda- Correspondence to: Professor Zhiwen Xu, Department of mentally important roles in mesothelioma. Computer Science and Technology, Jilin University, 2699 Qianjin Previous studies have demonstrated that miRNA target Street, Changchun, Jilin 130012, P.R. China genes that regulate various biological processes, which has E‑mail: [email protected] provided a database consisting of large amounts of experimen- tally validated data (7‑13). The genes that miRNA are located Abbreviations: miRNA, microRNA; TFs, transcription factors; Targets, target genes; TFBSs, transcription factor binding sites; on are referred to miRNA host genes. Rodriguez et al (14) indi- NCBI, National Center for Biotechnology Information cated that miRNA are transcribed in parallel with their host transcripts and two different transcription classes of miRNA, Key words: transcription factors, microRNA, target genes, host exonic and intronic, were identified. Baskerville et al (15) gene, network, mesothelioma demonstrated that intronic miRNA and its host gene are closely related. In the present study, when discussing differentially expressed miRNA, we considered its host genes to be mutated. 3040 ZHANG et al: REGULATORY NETWORK OF MESOTHELIOMA In the present study, experimentally validated data on between TFs and miRNA were collated (20). The TransmiR differentially expressed factors and related factors were database catalogues data extracted from public literature and manually collated from various literature sources and data- biological experiments. This dataset was assigned as U2. bases. These experimentally validated relations concerned genes regulating miRNA and miRNA located on host genes or miRNA‑host gene dataset. Data on the host genes of targeting target genes. These regulatory relations were chosen human miRNA were manually extracted from miRBase as they were considered them to be a basic resource for the (mirbase.org/) and NCBI (21). Subsequently, their official construction of three networks to reveal the regulatory mech- symbols and IDs were unified to those outlined by NCBI. anism in mesothelioma. The three regulatory networks were This dataset was assigned as U3. as follows: i) DEGs and miRNA; ii) predominantly related genes and miRNA; and iii) a global network constructed from Construction of three level networks. all data associated with mesothelioma. Nodes and pathways Differentially expressed network of mesothelioma. DEGs in three networks were analyzed in order to identify those and miRNA are genes that are not properly expressed. Their with valuable regulatory relationships in mesothelioma. The misregulation directly leads to the formation of mesothe- findings of the present study may aid further elucidation of the lioma; therefore, each node and pathway was examined. As pathogenesis of mesothelioma. outlined, the obtained mutated factors were assigned as the nodes in the network. Subsequently, these nodes were mapped Materials and methods onto the U1, U2 and U3 datasets to extract the regulatory rela- tion as the edges in the network. After all relationships were Mutated genes in mesothelioma. Data on mutated genes combined, the core misregulation network of mesothelioma were collected from the National Center for Biotechnology was established. Information single nucleotide polymorphism data- base (ncbi.nlm.nih.gov/snp/), Cancer Genetics Web Related network of mesothelioma. The function of related (cancerindex.org/geneweb/index.html), the Science Citation factors, which also affect regulatory relationships, should Index and the Kyoto Encyclopedia of Genes and Genomes not be neglected. Therefore, a network of related genes and pathway database (genome.jp/kegg/pathway.html). miRNA was constructed to further elucidate the regulatory mechanism of mesothelioma. Certainly, it contains more Related genes in mesothelioma. Data on all the genes related regulatory relations than the core network. The construction to mesothelioma were collected via three methods. Firstly, of this network was similar to the differentially expressed the SCI papers about mesothelioma were reviewed to collect network. The related elements were mapped onto U1, U2 and the names of the genes related to mesothelioma. Secondly, U3, and the regulatory relationships among TF, targets and the related genes were searched on the GeneCards database host genes associated with miRNA in mesothelioma were (genecards.org/) (16), and the genes ranked within the top subsequently extracted. 200 were saved. Thirdly, popular TFs were identified using the P‑match method (17). The steps were as follows: 1,000 nt Global network of mesothelioma. In the third network, all promoter region sequences of the targets of DEGs were down- the obtained genes and miRNA were mapped onto U1, U2 loaded from the UCSC database (genome.ucsc.edu/) (18), and and U3, and the regulatory relationships among TF‑miRNA, the P‑match method was subsequently used, as it combines target‑miRNA and host‑miRNA were extracted. Following pattern matching and weight matrices approaches to iden- integration of all the relationships, the global network of tify TF binding sites (TFBSs) in 1,000 nt promoter region mesothelioma was established. sequences and maps the TFBSs onto promoter regions of targets. These TFs found by P‑Match were also added to the Results and Discussion file, as were mutated genes of mesothelioma. Differentially expressed network of mesothelioma. Fig. 1 Differently expressed miRNA in mesothelioma. Differentially presents the important regulatory relationships of differ- expressed miRNA were extracted from a manually curated entially expressed factors in mesothelioma, composed of database named mir2Disease (mir2disease.org/), which five TFs [tumor protein 53 (TP53), phosphatase and tensin catalogues differentially expressed miRNA in various human homolog (PTEN), E2F1, nuclear
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