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Integrated Bioinformatics Analysis of Hub Genes and Pathways in Anaplastic Thyroid Carcinomas.

ABSTRACT: Anaplastic thyroid carcinoma (ATC) is a very rare malignancy; the pathogenesis of which is still not fully understood. The aim of the present study was to identify hub genes and pathways in ATC by microarray expression profiling. Two independent datasets (GSE27155 and GSE53072) were downloaded from GEO database. The differentially expressed genes (DEGs) between ATC tissues and normal thyroid tissues were screened out by the limma package and then enriched by gene ontology (GO) and KEGG pathway analysis. The hub genes were selected by protein-protein interaction (PPI) analysis. A total of 141 common upregulated and 87 common downregulated genes were screened out. These DEGs were significantly enriched in the phagosome and NF-kappa B signaling pathway. Through PPI analysis, TOP2A, TYMS, CCNB1, RACGAP1, FEN1, PRC1, and UBE2C were selected as hub genes, which were highly expressed in ATC tissues. TCGA data suggested that the expression levels of TOP2A, TYMS, FEN1, and PRC1 genes were also upregulated in other histological subtypes of thyroid carcinoma. High expression of TOP2A, TYMS, FEN1, PRC1, or UBE2C gene significantly decreased disease-free survival of patients with other thyroid carcinomas. In conclusion, the present study identified several hub genes and pathways, which will contribute to elucidating the pathogenesis of ATC and providing therapeutic targets for ATC.

SUBMITTER: Gao X

PROVIDER: S-EPMC6350566 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Integrated Bioinformatics Analysis of Hub Genes and Pathways in Anaplastic Thyroid Carcinomas.

Gao Xueren X Wang Jianguo J Zhang Shulong S

International journal of endocrinology 20190113

Anaplastic thyroid carcinoma (ATC) is a very rare malignancy; the pathogenesis of which is still not fully understood. The aim of the present study was to identify hub genes and pathways in ATC by microarray expression profiling. Two independent datasets (GSE27155 and GSE53072) were downloaded from GEO database. The differentially expressed genes (DEGs) between ATC tissues and normal thyroid tissues were screened out by the limma package and then enriched by gene ontology (GO) and KEGG pathway a ...[more]

PMID: 30774662

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Project description:BACKGROUND To provide a better understanding of anaplastic thyroid carcinoma (ATC) at the molecular level, this study aimed to identify the genes and key pathways associated with ATC by using integrated bioinformatics analysis. MATERIAL AND METHODS Based on the microarray data GSE9115, GSE65144, and GSE53072 derived from the Gene Expression Omnibus, the differentially expressed genes (DEGs) between ATC samples and normal controls were identified. With DEGs, we performed a series of functional enrichment analyses. Then, a protein-protein interaction (PPI) network was constructed and visualized, with which the hub gene nodes were screened out. Finally, modules analysis for the PPI network was performed to further investigate the potential relationships between DEGs and ATC. RESULTS A total of 537 common DEGs were screened out from all 3 datasets, among which 247 genes were upregulated and 275 genes were downregulated. GO analysis indicated that upregulated DEGs were mainly involved in cell division and mitotic nuclear division and the downregulated DEGs were significantly enriched in ventricular cardiac muscle cell action potential. KEGG pathway analysis showed that the upregulated DEGs were mainly enriched in cell cycle and ECM-receptor interaction and the downregulated DEGs were mainly enriched in thyroid hormone synthesis, insulin resistance, and pathways in cancer. The top 10 hub genes in the constructed PPI network were CDK1, CCNB1, TOP2A, AURKB, CCNA2, BUB1, AURKA, CDC20, MAD2L1, and BUB1B. The modules analysis showed that genes in the top 2 significant modules of PPI network were mainly associated with mitotic cell cycle and positive regulation of mitosis, respectively. CONCLUSIONS We identified a series of key genes along with the pathways that were most closely related with ATC initiation and progression. Our results provide a more detailed molecular mechanism for the development of ATC, shedding light on the potential biomarkers and therapeutic targets.

Project description:Anaplastic thyroid carcinoma (ATC) is one of the most aggressive and rapidly lethal tumors. However, limited advances have been made to prolong the survival and to reduce the mortality over the last decades. Therefore, identifying the master regulators underlying ATC progression is desperately needed. In our present study, three datasets including GSE33630, GSE29265, and GSE65144 were retrieved from Gene Expression Omnibus with a total of 32 ATC samples and 78 normal thyroid tissues. A total of 1804 consistently changed differentially expressed genes (DEGs) were identified from three datasets. KEGG pathways enrichment suggested that upregulated DEGs were mainly enriched in ECM-receptor interaction, cell cycle, PI3K-Akt signaling pathway, focal adhesion, and p53 signaling pathway. Furthermore, key gene modules in PPI network were identified by Cytoscape plugin MCODE and they were mainly associated with DNA replication, cell cycle process, collagen fibril organization, and regulation of leukocyte migration. Additionally, TOP2A, CDK1, CCNB1, VEGFA, BIRC5, MAPK1, CCNA2, MAD2L1, CDC20, and BUB1 were identified as hub genes of the PPI network. Interestingly, module analysis showed that 8 out of 10 hub genes participated in Module 1 network and more than 70% genes of Module 2 consisted of collagen family members. Notably, transcription factors (TFs) regulatory network analysis indicated that E2F7, FOXM1, and NFYB were master regulators of Module 1, while CREB3L1 was the master regulator of Module 2. Experimental validation showed that CREB3L1, E2F7, and FOXM1 were significantly upregulated in ATC tissue and cell line when compared with normal thyroid group. In conclusion, the TFs regulatory network provided a more detail molecular mechanism underlying ATC occurrence and progression. TFs including E2F7, FOXM1, CREB3L1, and NFYB were likely to be master regulators of ATC progression, suggesting their potential role as molecular therapeutic targets in ATC treatment.

Project description:BackgroundHepatocellular carcinoma (HCC), the main type of liver cancer in human, is one of the most prevalent and deadly malignancies in the world. The present study aimed to identify hub genes and key biological pathways by integrated bioinformatics analysis.MethodsA bioinformatics pipeline based on gene co-expression network (GCN) analysis was built to analyze the gene expression profile of HCC. Firstly, differentially expressed genes (DEGs) were identified and a GCN was constructed with Pearson correlation analysis. Then, the gene modules were identified with 3 different community detection algorithms, and the correlation analysis between gene modules and clinical indicators was performed. Moreover, we used the Search Tool for the Retrieval of Interacting Genes (STRING) database to construct a protein protein interaction (PPI) network of the key gene module, and we identified the hub genes using nine topology analysis algorithms based on this PPI network. Further, we used the Oncomine analysis, survival analysis, GEO data set and random forest algorithm to verify the important roles of hub genes in HCC. Lastly, we explored the methylation changes of hub genes using another GEO data (GSE73003).ResultsFirstly, among the expression profiles, 4,130 up-regulated genes and 471 down-regulated genes were identified. Next, the multi-level algorithm which had the highest modularity divided the GCN into nine gene modules. Also, a key gene module (m1) was identified. The biological processes of GO enrichment of m1 mainly included the processes of mitosis and meiosis and the functions of catalytic and exodeoxyribonuclease activity. Besides, these genes were enriched in the cell cycle and mitotic pathway. Furthermore, we identified 11 hub genes, MCM3, TRMT6, AURKA, CDC20, TOP2A, ECT2, TK1, MCM2, FEN1, NCAPD2 and KPNA2 which played key roles in HCC. The results of multiple verification methods indicated that the 11 hub genes had highly diagnostic efficiencies to distinguish tumors from normal tissues. Lastly, the methylation changes of gene CDC20, TOP2A, TK1, FEN1 in HCC samples had statistical significance (P-value < 0.05).ConclusionMCM3, TRMT6, AURKA, CDC20, TOP2A, ECT2, TK1, MCM2, FEN1, NCAPD2 and KPNA2 could be potential biomarkers or therapeutic targets for HCC. Meanwhile, the metabolic pathway, the cell cycle and mitotic pathway might played vital roles in the progression of HCC.

Project description:Thyroid carcinoma (TC) is one of the most common types of endocrine neoplasm with poor prognosis due to its aggressive behavior. Biomarkers for early diagnosis and prevention of TC are in urgent demand. By using a bioinformatics analysis, the present study aimed to identify essential genes and pathways associated with TC. First, the GSE27155 and GSE50901 expression profiles were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were obtained using the two microarray datasets and further subjected to integrated analysis. A gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed 45 common DEGs in the two datasets. GO and KEGG pathway analysis indicated that the biological functions of the DEGs included protein binding, cardiac muscle cell potential involved in contraction, aldehyde dehydrogenase activity, the TGF-β receptor signaling pathway and the canonical Wnt signaling pathway. A protein-protein interaction network was also constructed and visualized to display the nodes of the top 9 up- and 36 downregulated common DEGs. The integrated bioinformatics analysis indicated that potassium inwardly rectifying channel subfamily J member 2 (KCNJ2) was the most significantly upregulated DEG. The transcriptional levels of KCNJ2 were confirmed to be elevated in TC tissues compared with those in normal tissues using reverse transcription-quantitative PCR analysis. Furthermore, the expression level of KCNJ2 was significantly associated with the 5-year survival rate of patients with TC, which was determined using the Kaplan-Meier method. In TC cell lines, KCNJ2 was also upregulated as compared with that in a normal control cell line. Finally, small interfering RNA was used to knock down the expression of KCNJ2, which was demonstrated to inhibit cell proliferation, migration and invasion, while increasing apoptosis in TC cells. In conclusion, in the present study, KCNJ2 was screened as an oncogene with a crucial role in TC development and progression and may represent a promising candidate biomarker and therapeutic target for TC.

Dataset Information

Integrated Bioinformatics Analysis of Hub Genes and Pathways in Anaplastic Thyroid Carcinomas.

Publications

Integrated Bioinformatics Analysis of Hub Genes and Pathways in Anaplastic Thyroid Carcinomas.

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