Integrated Analysis of Copy Number Variations and Gene Expression Profiling in Hepatocellular carcinoma

Zhou, Chixing; Zhang, Wentao; Chen, Wanyong; Yin, Yuehui; Atyah, Manar; Liu, Shuang; Guo, Lei; Shi, Yi; Ye, Qing–Hai; Dong, Qiongzhu; Ren, Ning

doi:10.1038/s41598-017-11029-y

Cited by 37 publications

(28 citation statements)

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“…By data mining, we observed increased DNA copy number of Exo1 in HCC, in agreement with previous findings that the chromosomal region 1q, especially 1q42.12 and 1q43, has frequent copy number gains in more than 65% of HCC cases [32]. This finding prompted us to assess the expression levels of EXO1 in HCC, which remain unknown, since copy number variation (CNV) is an important genetic aberration and leads to the activation of oncogenes in cancer [33]. Moreover, a possible mechanism of chromosome abnormalities responsible for EXO1 gene upregulation other than modulation at the transcription and post-translation levels could be demonstrated [34,35].…”

Section: Discussionsupporting

confidence: 88%

EXO1 overexpression is associated with poor prognosis of hepatocellular carcinoma patients

et al. 2018

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The roles of exonuclease 1 (EXO1) in hepatocellular carcinoma (HCC) tumorigenesis and progression remain unclear. This study aimed to assess the prognostic value and therapeutic potential of EXO1 in HCC. Exo1 gene copy numbers were obtained from three Oncomine microarray datasets (n = 447). EXO1 mRNA expression was validated by semi-quantitative PCR and QuantiGene® 2.0 assays. Cell growth curve and colony formation were performed to asses the cell proliferation. Clonogenic assay, flow cytometry, and immunofluorescence were adopted to acess the effects of EXO1 knockdown and radiation on cell survival, cell cycle distribution and DNA repair. Western blots were performed to reveal the related mechanism. A significant copy number variation (CNV) of the Exo1 gene was found in HCC specimens in three separate sets of published microarray data. In the 143 cases treated by our team, EXO1 expression levels were elevated (86.71%, 124/143). In addition, EXO1 overexpression was correlated with larger tumor size (P = 0.002), increased lymph node metastasis (P=0.033) and lower Edmondson grade (P = 0.018). High EXO1 expression unfavorably affected overall survival (OS) (P = 0.009). Both univariate and multivariate Cox regression analyses identified EXO1 as an independent predictor of OS (univariate, P = 0.012; multivariate, P = 0.039). Silencing of EXO1 in vitro reduced cell proliferation. EXO1 knockdown further suppressed clonogenic cell survival, abrogated radiation-induced G2/M phase arrest, and enhanced γ-H2AX foci after exposure to irradiation. The accumulation of ataxiatelangiectasia mutated (ATM) might partially regulate the EXO1 related radiosensitivity. In summary, EXO1 could be a promising prognostic marker, with a potential therapeutic value in HCC.

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Section: Discussionsupporting

confidence: 88%

EXO1 overexpression is associated with poor prognosis of hepatocellular carcinoma patients

et al. 2018

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“…In accordance with our findings, previous studies have also identified DEGs that participate 320 in HBV-related liver cancer (Zhou et al, 2017). For example, Zhou et al analyzed the gene 321 expression profiles of GSE14520 and HCC samples from the Zhongshan Hospital affiliated with 322 Fudan University, which comprised 63 paired HCC and non-tumor samples.…”

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confidence: 83%

Peer Review #1 of "Identification of significant gene and pathways involved in HBV-related hepatocellular carcinoma by bioinformatics analysis (v0.1)"

Módos¹

2019

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Background: Hepatocellular carcinoma (HCC) is a common malignant tumor affecting the digestive system and causes serious financial burden worldwide. Hepatitis B virus (HBV) is the main causative agent of HCC in China. The present study aimed to investigate the potential mechanisms underlying HBV-related HCC and to identify core biomarkers by integrated bioinformatics analyses. Methods: In the present study, HBV-related HCC GSE19665, GSE55092, GSE94660 and GSE121248 expression profiles were downloaded from the Gene Expression Omnibus database. These databases contain data for 299 samples, including 145 HBV-related HCC tissues and 154 non-cancerous tissues (from patients with chronic hepatitis B). The differentially expressed genes (DEGs) from each database were integrated and analyzed using the RobustRankAggreg (RRA) method and R software, and the integrated DEGs were identified. Subsequently, the gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed using the DAVID online tool, and the protein-protein interaction (PPI) network was constructed using STRING and visualized using Cytoscape software.Finally, hub genes were identified, and the cBioPortal online platform was used to analyze the association between the expression of hub genes and prognosis in HBV-related HCC.Results: First, 341 DEGs (117 upregulated and 224 downregulated) were identified from the four datasets. Next, GO analysis showed that the upregulated genes were mainly involved in cell cycle, mitotic spindle, and adenosine triphosphate binding. The majority of the downregulated genes were involved in oxidation reduction, extracellular region, and electron carrier activity. Signaling pathway analysis showed that the integrated DEGs shared common pathways in retinol metabolism, drug metabolism, tryptophan metabolism, caffeine metabolism, and metabolism of xenobiotics by cytochrome P450. The integrated DEG PPI network complex comprised 288 nodes, and two important modules PeerJ reviewing PDF | Manuscript to be reviewed with high degree were detected using the MCODE plug-in. The top ten hub genes identified from the PPI network were SHCBP1, FOXM1, KIF4A, ANLN, KIF15, KIF18A, FANCI, NEK2, ECT2, and RAD51AP1. Finally, survival analysis revealed that patients with HBV-related HCC showing altered ANLN and KIF18A expression profiles showed worse disease-free survival. Nonetheless, patients with FOXM1, NEK2, RAD51AP1, ANLN, and KIF18A alterations showed worse overall survival. Conclusions: The present study identified key genes and pathways involved in HBV-related HCC, which improved our understanding of the mechanisms underlying the development and recurrence of HCC and identified candidate targets for the diagnosis and treatment of HBV-related HCC.PeerJ reviewing PDF | Abstract 16 Background: Hepatocellular carcinoma (HCC) is a common malignant tumor affecting the 17 digestive system and causes serious financial burden worldwide. Hepatitis B virus (HBV) is the 18 main causative agent of H...

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“…In human, CNVs have been implicated in numerous diseases, such as autism and diabetes [ 12 , 13 ]. CNVs also contribute significantly to the genome instability of cancer cells [ 14 – 16 ]. For example, recently, Pelttari [ 14 ] reported a unique duplication encompassing most of the RAD51 homolog C gene in breast and ovarian cancers.…”

Section: Introductionmentioning

confidence: 99%

The correlation of copy number variations with longevity in a genome-wide association study of Han Chinese

Zhao

Liu

Zhang

et al. 2018

Aging

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Copy number variations (CNVs) have been shown to cause numerous diseases, however, their roles in human lifespan remain elusive. In this study, we investigate the association of CNVs with longevity by comparing the Han Chinese genomes of long-lived individuals from 90 to 117 years of age and the middle-aged from 30 to 65. Our data demonstrate that the numbers of CNVs, especially deletions, increase significantly in a direct correlation with longevity. We identify eleven CNVs that strongly associate with longevity; four of them locate in the chromosome bands, 7p11.2, 20q13.33, 19p12 and 8p23.3 and overlap partially with the CNVs identified in long-lived Danish or U.S. populations, while the other seven have not been reported previously. These CNV regions encode nineteen known genes, and some of which have been shown to affect aging-related phenotypes such as the shortening of telomere length (ZNF208), the risk of cancer (FOXA1, LAMA5, ZNF716), and vascular and immune-related diseases (ARHGEF10, TOR2A, SH2D3C). In addition, we found several pathways enriched in long-lived genomes, including FOXA1 and FOXA transcription factor networks involved in regulating aging or age-dependent diseases such as cancer. Thus, our study has identified longevity-associated CNV regions and their affected genes and pathways. Our results suggest that the human genome structures such as CNVs might play an important role in determining a long life in human.

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Integrated Analysis of Copy Number Variations and Gene Expression Profiling in Hepatocellular carcinoma

Cited by 37 publications

References 50 publications

EXO1 overexpression is associated with poor prognosis of hepatocellular carcinoma patients

EXO1 overexpression is associated with poor prognosis of hepatocellular carcinoma patients

Peer Review #1 of "Identification of significant gene and pathways involved in HBV-related hepatocellular carcinoma by bioinformatics analysis (v0.1)"

The correlation of copy number variations with longevity in a genome-wide association study of Han Chinese

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