Hepatitis B virus X protein (HBx) induces G2/M arrest and apoptosis through sustained activation of cyclin B1-CDK1 kinase

Cheng, Ping; Li, Yuhua; Yang, Liping; Shi, Wei; Mao, Yong-Qiu; Chen, Ping; Lv, Huimin; Tang, Qingqing; Wei, Yuquan

doi:10.3892/or_00000542

Cited by 30 publications

(6 citation statements)

References 24 publications

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“…Previous studies have shown that CDK1/CCNB1 inhibits the p53 signaling pathway and regulate the development of HCC [ 8 ]. An in vitro study demonstrated that HBV X protein (HBx) induces G2/M phase arrest and apoptosis through continuous activation of CDK1/CCNB1 kinase [ 31 ]. Other studies reported that both CCNB1 and CDK1 are overexpressed in HBV-related HCC tissues and are associated with poor survival [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis of Candidate Genes and Pathways Related to Hepatocellular Carcinoma in China: A Study Based on Public Databases

Zhang¹,

Feng²,

Wu³

et al. 2021

Pathol. Oncol. Res.

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Background and Objective: Hepatocellular carcinoma (HCC) is a highly aggressive malignant tumor of the digestive system worldwide. Chronic hepatitis B virus (HBV) infection and aflatoxin exposure are predominant causes of HCC in China, whereas hepatitis C virus (HCV) infection and alcohol intake are likely the main risk factors in other countries. It is an unmet need to recognize the underlying molecular mechanisms of HCC in China.Methods: In this study, microarray datasets (GSE84005, GSE84402, GSE101685, and GSE115018) derived from Gene Expression Omnibus (GEO) database were analyzed to obtain the common differentially expressed genes (DEGs) by R software. Moreover, the gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed by using Database for Annotation, Visualization and Integrated Discovery (DAVID). Furthermore, the protein-protein interaction (PPI) network was constructed, and hub genes were identified by the Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape, respectively. The hub genes were verified using Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, and Kaplan-Meier Plotter online databases were performed on the TCGA HCC dataset. Moreover, the Human Protein Atlas (HPA) database was used to verify candidate genes’ protein expression levels.Results: A total of 293 common DEGs were screened, including 103 up-regulated genes and 190 down-regulated genes. Moreover, GO analysis implied that common DEGs were mainly involved in the oxidation-reduction process, cytosol, and protein binding. KEGG pathway enrichment analysis presented that common DEGs were mainly enriched in metabolic pathways, complement and coagulation cascades, cell cycle, p53 signaling pathway, and tryptophan metabolism. In the PPI network, three subnetworks with high scores were detected using the Molecular Complex Detection (MCODE) plugin. The top 10 hub genes identified were CDK1, CCNB1, AURKA, CCNA2, KIF11, BUB1B, TOP2A, TPX2, HMMR and CDC45. The other public databases confirmed that high expression of the aforementioned genes related to poor overall survival among patients with HCC.Conclusion: This study primarily identified candidate genes and pathways involved in the underlying mechanisms of Chinese HCC, which is supposed to provide new targets for the diagnosis and treatment of HCC in China.

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Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis of Candidate Genes and Pathways Related to Hepatocellular Carcinoma in China: A Study Based on Public Databases

Zhang¹,

Feng²,

Wu³

et al. 2021

Pathol. Oncol. Res.

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“…UGT1A4, CYP2A6, CSF2, INRS, GSTM1, and BMP6 had the lowest relevance score of 20.08, 20.03, 20.47, 20.02, 20.0, and 20.02, respectively. The list of genes/protein molecules regulated by the HBV and each chemical-induced hepatitis which is obtained from a peer review of the literature (along with references [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , ...…”

Section: Resultsmentioning

confidence: 99%

System Biology Investigation Revealed Lipopolysaccharide and Alcohol-Induced Hepatocellular Carcinoma Resembled Hepatitis B Virus Immunobiology and Pathogenesis

Patil

Harish²,

Sampat

et al. 2023

IJMS

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Hepatitis B infection caused by the hepatitis B virus is a life-threatening cause of liver fibrosis, cirrhosis, and hepatocellular carcinoma. Researchers have produced multiple in vivo models for hepatitis B virus (HBV) and, currently, there are no specific laboratory animal models available to study HBV pathogenesis or immune response; nonetheless, their limitations prevent them from being used to study HBV pathogenesis, immune response, or therapeutic methods because HBV can only infect humans and chimpanzees. The current study is the first of its kind to identify a suitable chemically induced liver cirrhosis/HCC model that parallels HBV pathophysiology. Initially, data from the peer-reviewed literature and the GeneCards database were compiled to identify the genes that HBV and seven drugs (acetaminophen, isoniazid, alcohol, D-galactosamine, lipopolysaccharide, thioacetamide, and rifampicin) regulate. Functional enrichment analysis was performed in the STRING server. The network HBV/Chemical, genes, and pathways were constructed by Cytoscape 3.6.1. About 1546 genes were modulated by HBV, of which 25.2% and 17.6% of the genes were common for alcohol and lipopolysaccharide-induced hepatitis. In accordance with the enrichment analysis, HBV activates the signaling pathways for apoptosis, cell cycle, PI3K-Akt, TNF, JAK-STAT, MAPK, chemokines, NF-kappa B, and TGF-beta. In addition, alcohol and lipopolysaccharide significantly activated these pathways more than other chemicals, with higher gene counts and lower FDR scores. In conclusion, alcohol-induced hepatitis could be a suitable model to study chronic HBV infection and lipopolysaccharide-induced hepatitis for an acute inflammatory response to HBV.

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“…G2/mitotic-specific cyclin-B1 (CCNB1) was a major activator of CDK1 [ 31 ]. Studies showed that HBV activated CCNB1-CDK1 kinase in HCC cells in vitro [ 32 ]. CCNB1 and CDK1 were upregulated in HCC tissues of HBV-positive patients [ 33 ], and overexpression of CCNB1 and CDK1 was associated with poor prognosis [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

A systematic study on the treatment of hepatitis B-related hepatocellular carcinoma with drugs based on bioinformatics and key target reverse network pharmacology and experimental verification

Hao

et al. 2023

Infect Agents Cancer

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Background Chronic hepatitis B virus (HBV) infection is the major etiology of hepatocellular carcinoma (HCC). However, the mechanism of hepatitis B-related hepatocellular carcinoma (HBV-related HCC) is still unclear. Therefore, understanding the pathogenesis and searching for drugs to treat HBV-related HCC was an effective strategy to treat this disease. Purpose Bioinformatics was used to predict the potential targets of HBV-related HCC. The reverse network pharmacology of key targets was used to analyze the clinical drugs, traditional Chinese medicine (TCM) and small molecules of TCM in the treatment of HBV-related HCC. Methods In this study, three microarray datasets totally containing 330 tumoral samples and 297 normal samples were selected from the GEO database. These microarray datasets were used to screen DEGs. And the expression profile and survival of 6 key genes were analyzed. In addition, Comparative Toxicogenomics Database and Coremine Medical database were used to enrich clinical drugs and TCM of HBV-related HCC by the 6 key targets. Then the obtained TCM were classified based on the Chinese Pharmacopoeia. Among these top 6 key genes, CDK1 and CCNB1 had the most connection nodes and the highest degree and were the most significantly expressed. In general, CDK1 and CCNB1 tend to form a complex, which is conducive to cell mitosis. Hence, this study mainly studied CDK1 and CCNB1. HERB database was used to predict small molecules TCM. The inhibition effect of quercetin, celastrol and cantharidin on HepG2.2.15 cells and Hep3B cells was verified by CCK8 experiment. The effects of quercetin, celastrol and cantharidin on CDK1 and CCNB1 of HepG2.2.15 cells and Hep3B cells were determined by Western Blot. Results In short, 272 DEGs (53 upregulated and 219 downregulated) were identified. Among these DEGs, 6 key genes with high degree were identified, which were AURKA, BIRC5, CCNB1, CDK1, CDKN3 and TYMS. Kaplan–Meier plotter analysis showed that higher expression levels of AURKA, BIRC5, CCNB1, CDK1, CDKN3 and TYMS were associated with poor OS. According to the first 6 key targets, a variety of drugs and TCM were identified. These results showed that clinical drugs included targeted drugs, such as sorafenib, palbociclib and Dasatinib. and chemotherapy drugs, such as cisplatin and doxorubicin. TCM, such as the TCM flavor was mainly warm and bitter, and the main meridians were liver and lung. Small molecules of TCM included flavonoids, terpenoids, alkaloids and glycosides, such as quercetin, celastrol, cantharidin, hesperidin, silymarin, casticin, berberine and ursolic acid, which have great potential in anti-HBV-related HCC. For molecular docking of chemical components, the molecules with higher scores were flavonoids, alkaloids, etc. Three representative types of TCM small molecules were verified respectively, and it was found that quercetin, celastrol and cantharidin inhibited the proliferation of HepG2.2.15 cells and Hep3B cells along concentration gradient. Quercetin, celastrol and cantharidin decreased CDK1 expression in HepG2.2.15 and Hep3B cells, but for CCNB1, only cantharidin decreased CCNB1 expression in the two strains of cells. Conclusion In conclusion, AURKA, BIRC5, CCNB1, CDK1, CDKN3 and TYMS could be potential targets for the diagnosis and prognosis of HBV-related HCC. Clinical drugs include chemotherapeutic and targeted drug, traditional Chinese medicine is mainly bitter and warm TCM. Small molecular of TCM including flavonoids, terpenoids and glycosides and alkaloids, which have great potential in anti-HBV-related HCC. This study provides potential therapeutic targets and novel strategies for the treatment of HBV-related HCC.

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Hepatitis B virus X protein (HBx) induces G2/M arrest and apoptosis through sustained activation of cyclin B1-CDK1 kinase

Cited by 30 publications

References 24 publications

Bioinformatics Analysis of Candidate Genes and Pathways Related to Hepatocellular Carcinoma in China: A Study Based on Public Databases

Bioinformatics Analysis of Candidate Genes and Pathways Related to Hepatocellular Carcinoma in China: A Study Based on Public Databases

System Biology Investigation Revealed Lipopolysaccharide and Alcohol-Induced Hepatocellular Carcinoma Resembled Hepatitis B Virus Immunobiology and Pathogenesis

A systematic study on the treatment of hepatitis B-related hepatocellular carcinoma with drugs based on bioinformatics and key target reverse network pharmacology and experimental verification

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