scholarly journals Identification and validation of three core genes in p53 signaling pathway in hepatitis B virus-related hepatocellular carcinoma

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Mingxue Yu ◽  
Wenli Xu ◽  
Yusheng Jie ◽  
Jiahui Pang ◽  
Siqi Huang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Enrichment Analysis ◽  
Normal Liver ◽  
Validation Dataset ◽  
P53 Signaling ◽  
B Virus ◽  
P53 Signaling Pathway ◽  
Core Genes

Abstract Background Hepatocellular carcinoma (HCC) is a common cancer and the leading cause is persistent hepatitis B virus (HBV) infection. We aimed to identify some core genes and pathways for HBV-related HCC. Methods Gene expression profiles of GSE62232, GSE121248, and GSE94660 were available from Gene Expression Omnibus (GEO). The GSE62232 and GSE121248 profiles were the analysis datasets and GSE94660 was the validation dataset. The GEO2R online tool and Venn diagram software were applied to analyze commonly differentially expressed genes between HBV-related HCC tissues and normal tissues. Then, functional enrichment analysis using Gene Ontology (GO) and the Kyoto Encyclopedia of Gene and Genome (KEGG) as well as the protein-protein interaction (PPI) network was conducted. The overall survival rates and the expression levels were detected by Kaplan-Meier plotter and Gene Expression Profiling Interactive Analysis (GEPIA). Next, gene set enrichment analysis (GSEA) was performed to verify the KEGG pathway analysis. Furthermore, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was performed to validate the levels of these three core genes in tumor tissues and adjacent non-tumor liver tissues from 12 HBV related HCC patients, HBV-associated liver cancer cell lines and normal liver cell lines, and HepG2 with p53 knockdown or deletion, respectively. Results Fifteen highly expressed genes associated with significantly worse prognoses were selected and CCNB1, CDK1, and RRM2 in the p53 signaling pathway were identified as core genes. GSEA results showed that samples highly expressing three core genes were all enriched in the p53 signaling pathway in a validation dataset (P < 0.0001). The expression of these three core genes in tumor tissue samples was higher than that in relevant adjacent non-tumor liver tissues (P < 0.0001). Furthermore, we also found that the above genes were highly expressed in liver cancer cell lines compared with normal liver cells. In addition, we found that the expression of these three core genes in p53 knockdown or knockout HCC cell lines was lower than that in negative control HCC cell lines (P < 0.05). Conclusions CCNB1, CDK1, and RRM2 were enriched in the p53 signaling pathway and could be potential biomarkers and therapeutic targets for HBV-related HCC.

scholarly journals Identification and Validation of Three Core Genes in p53 Signaling Pathway in Hepatitis B Virus-Related Hepatocellular Carcinoma

2020 ◽  
Author(s):  
Mingxue Yu ◽  
Wenli Xu ◽  
Yusheng Jie ◽  
Jiahui Pang ◽  
Siqi Huang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Liver Cancer ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Liver Cancer Cell ◽  
P53 Signaling ◽  
P53 Signaling Pathway ◽  
Core Genes

Abstract Background：Hepatocellular carcinoma (HCC) is a common cancer and the leading cause is persistent hepatitis B virus infection. We aimed to identify some core genes and pathways for HBV-related HCC. Methods: Gene expression profiles of GSE62232, GSE121248, and GSE94660 were available from Gene Expression Omnibus. The GEO2R online tool and Venn diagram software were applied to analyze commonly differentially expressed genes. Then functional enrichment analysis using Gene Ontology (GO) and the Kyoto Encyclopedia of Gene and Genome (KEGG) as well as the protein-protein interaction (PPI) network was conducted. The overall survival rates and the expression levels were detected by Kaplan-Meier plotter and Gene Expression Profiling Interactive Analysis (GEPIA). Next, gene set enrichment analysis (GSEA) was performed to verify the KEGG pathway analysis. Furthermore, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was performed to validate the levels of gene expression in tumor tissues from HBV related HCC patients, HBV-related liver cell lines, and transfection si-p53 and knock-out p53 liver cancer cell lines. Finally, the prediction of the ceRNA network was constructed with R software. Results: Fifteen highly expressed genes associated with significantly worse prognoses were selected and CCNB1, CDK1, and RRM2 in the p53 signaling pathway were identified as core genes. GSEA results showed highly-expressed samples of three core genes were all enriched in the p53 signaling pathway in a validation dataset(P<0.0001). Expression of these three core genes were consistently higher in tumor tissue samples (P<0.0001) and liver cancer cell lines (P<0.05). However, transfection si-p53 and knock-out p53 liver cancer cell lines had lower expression (P<0.05). LncRNAs, including NEAT1, MALAT1, XIST, AC021078.1, and SNHG16, were identified by close interactions with core genes. Conclusions: CCNB1, CDK1, and RRM2 were enriched in the p53 signaling pathway and could be potential biomarkers and therapeutic targets for HBV-related HCC.

scholarly journals Blood Gene Expression Profile Study Revealed the Activation of Apoptosis and p53 Signaling Pathway May Be the Potential Molecular Mechanisms of Ionizing Radiation Damage and Radiation-Induced Bystander Effects

Dose-Response ◽  
2020 ◽  
Vol 18 (1) ◽  
pp. 155932582091418
Author(s):  
Guangyao He ◽  
Anzhou Tang ◽  
Mao Xie ◽  
Wei Xia ◽  
Pengcheng Zhao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Network Analysis ◽  
Ionizing Radiation ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Enrichment Analysis ◽  
P53 Signaling ◽  
Gene Correlation ◽  
Radiation Induced ◽  
P53 Signaling Pathway

Radiotherapy is an effective treatment for local solid tumors, but the mechanism of damage to human body caused by radiation therapy needs further study. In this study, gene expression profiles of human peripheral blood samples exposed to different doses and rates of ionizing radiation (IR) were used for bioinformatics analysis to investigate the mechanism of IR damage and radiation-induced bystander effect (RIBE). Differentially expressed genes analysis, weighted gene correlation network analysis, functional enrichment analysis, hypergeometric test, gene set enrichment analysis, and gene set variation analysis were applied to analyze the data. Moreover, receiver operating characteristic curve analysis was performed to identify core genes of IR damage. Weighted gene correlation network analysis identified 3 modules associated with IR damage, 2 were positively correlated and 1 was negatively correlated. The analysis showed that the positively correlated modules were significantly involved in apoptosis and p53 signaling pathway, and ESR1, ATM, and MYC were potential transcription factors regulating these modules. Thus, the study suggested that apoptosis and p53 signaling pathway may be the potential molecular mechanisms of IR damage and RIBE, which could be driven by ESR1, ATM, and MYC.

Dysregulation, But Not Mutation Of p53 Signaling Pathway In Breast Implant-Associated Anaplastic Large Cell Lymphoma Cell Lines

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4879-4879 ◽  
Author(s):  
Hai Wang ◽  
Chao Xie ◽  
Shiwu Li ◽  
Eva V. George ◽  
Westley H. Reeves ◽  
...  
Keyword(s):  
Dna Damage ◽  
Signaling Pathway ◽  
Cell Lines ◽  
P53 Protein ◽  
Breast Implant ◽  
Large Cell ◽  
Qrt Pcr ◽  
P53 Signaling ◽  
P53 Activation ◽  
P53 Signaling Pathway

Abstract A consistent feature of over 100 reported cases of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is their complex cytogenetic abnormalities, suggesting that genomic instability may drive lymphomagenesis and/or tumor progression. Loss of heterozygosity(LOH) of the TP53 tumor suppressor gene locus on the short arm of chromosome 17 (17p13.1) is a frequent finding. Human p53 plays an important role in cell cycle arrest, DNA repair, and apoptosis and it maintains genome stability by preventing mutations. Recently, three T cell breast lymphoma (TLBR) cell lines were derived from patients’ BIA-ALCL primary tumor biopsy specimens. These cell lines are IL-2 dependent, ALK-negative, CD30+activated cytotoxic T cells closely resembling the original tumor cells. Thus, the cell lines may serve as an important tool for studying this newly recognized disease entity. Because of its rarity, the clinical pathologic features, tumor cell biology, and genetics of BIA-ALCL have yet to be fully defined. Here we tested the hypothesis that the p53 signaling pathway is defective in TLBR cells. We initially examined TP53 transcript expression among the cell lines. By qRT-PCR, p53 transcripts were detected in all three lines, with the highest level in TLBR-2. Next we examined p53 protein expression and p53 activation in response to ultraviolet (UV) or gamma irradiation. By Western blotting, all TLBR cell lines expressed much lower levels of p53 protein following UV irradiation (400 J/m2) than Karpas (ALK+ ALCL) cells and failed to show ATM/ATR-induced phosphorylation of p53 on serine 15, an early indicator of p53 activation. Genetic defects (deletion, mutation) of the p53 coding sequence were not found by Sanger sequencing. Interestingly, a polymorphism at p53 codon 72 (Arg72Pro), a normal variant associated with increased susceptibility to breast cancer, was detected in TLBR-1 and -3 (derived from indolent BIA-ALCL), but not in the aggressive BIA-ALCL line TLBR-2. Thus, TLBR cells exhibit defective regulation of the p53 pathway in response to DNA damage, suggesting that their ability to sense DNA damage or the regulation of p53 stability may be impaired. We next examined the DNA damage sensing pathway upstream of p53 in the presence and absence of the DNA demethylating agent 5-aza-2'-deoxycytidine (AZA, 10µM for 48hrs). In all TLBR lines, ATM and ATR transcripts were expressed at much lower levels (qRT-PCR) than normal, and their expression was not significantly affected by AZA. However, compared with human T cells, CHK2 (phosphorylate P53 at Ser20) transcripts were very low in TLBR-1 and -2, but not in TLBR-3 cells. CHK2 and p21 (the main p53 target gene) transcripts after AZA were greatly increased in TLBR-2, mildly elevated in TLBR-3, and unchanged in TLBR-1 cells, suggesting that DNA methylation of the CHK2 and p21 genes may partly explain the defective p53 signaling in TLBR-2 cells. This was confirmed by detecting of CHK2 phorphrylation only in TLBR-3 cells. Mdm2, a major negative regulator of p53 protein stability, was either normal or low (qRT-PCR), and was unaffected by AZA. However, immunobloting with Mdm2 antibodies revealed increased levels of two isoforms following UV of TLBR-1 and -2, but only the small isoform was expressed in TLBR-3 cells and there was little response to UV treatment. Treatment of TLBR cells with 5 µM Nutlin-3 (Mdm2 antagonist, p53 activator, and apoptosis inducer) inhibited cell growth by 40% at day 5 (MTT assay). We conclude that these three BIA-ALCL derived cell lines share dysregulation of the p53 signaling pathway, which may contribute to the genomic instability characteristic of these BIA-ALCL cases. First two authors have equally contributed to this abstract. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Exploring the Mechanism of Baicalin Intervention in Breast Cancer Based on MicroRNA Microarrays and Bioinformatics Strategies

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Anqi Ge ◽  
Lifang Liu ◽  
Xian’guang Deng ◽  
Jun Luo ◽  
Yanghua Xu
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Breast Cancer Cells ◽  
Enrichment Analysis ◽  
Dependent Manner ◽  
P53 Signaling ◽  
Microrna Microarrays ◽  
P53 Signaling Pathway ◽  
Mcf 7

Objective. To explore the mechanism of baicalin intervention in breast cancer based on microRNA microarrays. Methods. The inhibitory rate of baicalin intervention in MCF-7 breast cancer cells was determined by MTT. Then, the miRNA microarrays were used to validate the key microRNAs. After that, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to validate microRNA, hsa-miR-15a, hsa-miR-100, hsa-miR-16, and hsa-miR-7t. Finally, the potential targets of these key microRNAs are predicted by miRWalk, and DAVID was utilized for gene ontology (GO) enrichment analysis and pathway enrichment analysis. Results. Baicalin may inhibit the proliferation of MCF-7 cells in a dose-dependent and time-dependent manner. The concentration of baicalin 150 μmol/L was determined for the subsequent miRNA chip research. A total of 92 upregulated microRNAs and 35 downregulated microRNAs were obtained. The upregulated miRNAs include hsa-miR-6799-5p, hsa-miR-6126, hsa-miR-4792, hsa-miR-6848-5p, hsa-miR-3197, hsa-miR-6779-5p, and hsa-miR -654-5p. The downregulated miRNAs include hsa-miR-3911, hsa-miR-504-5p, hsa-miR-30a-3p, hsa-miR-193b-3p, and hsa-miR-181b-5p. Then, differentially expressed miRNA was verified by qRT-PCR. The results showed that the expression of hsa-miR-15a, hsa-miR-100, hsa-miR-16, and hsa-let-7c was upregulated ( P < 0.05 ), which was consistent with the results of the miRNA microarray. The enrichment analysis showed that baicalin might regulate the DNA-templated proliferation, DNA-templated transcription, p53 signaling pathway, etc., of MCF-7 breast cancer cells through miRNA. Conclusion. Baicalin inhibits the proliferation of breast cancer cells. It may achieve antitumor effects through regulating microRNAs so as to affect the DNA replication (such as cellular response to DNA damage stimulus and DNA binding), RNA transcription (such as regulation of transcription, DNA-templated, transcription from RNA polymerase II promoter, and transcription factor binding), protein synthesis (such as mRNA binding, Golgi apparatus, and protein complex), endocytosis, pathways in cancer, p53 signaling pathway, and so on.

scholarly journals Small nucleolar RNA 42 promotes the growth of hepatocellular carcinoma through the p53 signaling pathway

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ganggang Wang ◽  
Jinghua Li ◽  
Ye Yao ◽  
Yingyi Liu ◽  
Peng Xia ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Therapeutic Target ◽  
Prognostic Biomarker ◽  
Ectopic Expression ◽  
Migration And Invasion ◽  
P53 Signaling ◽  
P53 Signaling Pathway

AbstractRecent studies show that small nucleolar RNAs (snoRNAs) play an important role in tumorigenesis. SNORA42 is a potential therapeutic target and prognostic biomarker for various cancers, and the aim of the present study was to investigate the function and clinical relevance of SNORA42 in hepatocellular carcinoma (HCC). We detected the expression levels of SNORA42 in HCC and normal liver tissue samples, as well as in tumor and hepatocyte-derived cell lines. SNORA42 was significantly upregulated in the HCC tissues and cells compared to the adjacent liver tissues and normal hepatocytes. Furthermore, overexpression of SNORA42 correlated with poor prognosis in the HCC patients. Knocking down SNORA42 in HCC cell lines decreased their proliferation, migration and invasion in vitro, and inhibited tumor growth and metastasis in vivo. In contrast, ectopic expression of SNORA42 promoted HCC cell proliferation and inhibited apoptosis. Mechanistically, SNORA42 exerted its oncogenic effects by targeting the p53 signaling pathway and cell cycle transition. In conclusion, SNORA42 acted as an oncogene in HCC and was a potential prognostic biomarker and therapeutic target.

The Molecular Docking of Flavonoids Isolated from Daucus carota as a Dual Inhibitor of MDM2 and MDMX

2020 ◽  
Vol 15 (2) ◽  
pp. 154-164 ◽  
Author(s):  
Ijaz Muhammad ◽  
Noor Rahman ◽  
Gul E. Nayab ◽  
Sadaf Niaz ◽  
Mohibullah Shah ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Cancer Therapy ◽  
Natural Product ◽  
Signaling Pathway ◽  
In Silico ◽  
P53 Protein ◽  
Dual Inhibitor ◽  
P53 Signaling ◽  
In Silico Studies ◽  
P53 Signaling Pathway

Background: Cancer is characterized by overexpression of p53 associated proteins, which down-regulate P53 signaling pathway. In cancer therapy, p53 activity can be restored by inhibiting the interaction of MDMX (2N0W) and MDM2 (4JGR) proteins with P53 protein. Objective: In the current, study in silico approaches were adapted to use a natural product as a source of cancer therapy. Methods: In the current study in silico approaches were adapted to use a natural product as a source of cancer therapy. For in silico studies, Chemdraw and Molecular Operating Environment were used for structure drawing and molecular docking, respectively. Flavonoids isolated from D. carota were docked with cancerous proteins. Result: Based on the docking score analysis, we found that compound 7 was the potent inhibitor of both cancerous proteins and can be used as a potent molecule for inhibition of 2N0W and 4JGR interaction with p53. Conclusion: Thus the compound 7 can be used for the revival of p53 signaling pathway function however, intensive in vitro and in vivo experiments are required to prove the in silico analysis.

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