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Centromere Protein F (CENPF) Serves as a Potential Prognostic Biomarker and Target for Human Hepatocellular Carcinoma.

ABSTRACT: Overexpression of Centromere Protein F (CENPF) is associated with tumorigenesis of many human malignant tumors. But the molecular mechanism and prognostic value of CENPF in patients with hepatocellular carcinoma (HCC) are still unclear. In this essay, expression of CENPF in HCC tumors were evaluated in a series of databases, including GEO, TCGA, Oncomine, GEPIA, The Human Protein Atlas and Kaplan-Meier plotter. It was apparent that mRNA and protein expression levels of CENPF were significantly increased in patients with HCC and were manifestly associated with the tumor stage of HCC. Aberrant expressions of CENPF were significantly linked with worse overall survival (OS) and progression-free survival (PFS) in HCC patients. Then, immunohistochemistry of CENPF in human HCC samples was carried out to suggest that CENPF protein was over-expressed in HCC tissues, compared with paired adjacent non-cancerous samples. And small interfering RNAs of CENPF in the human HepG2 cells were further performed to reveal that down-regulation of CENPF significantly inhibited cell proliferation, cell migration, and cell invasion, but slightly promoted cell apoptosis in human HepG2 cells. Moreover, the gene-set enrichment analysis (GSEA) was conducted to probe the biology process and molecular signaling pathway of CENPF in HCC. The GSEA analysis pointed out that CENPF was principally enriched in cell cycle and closely related to E2F1 and CDK1 in the regulation of cell cycle, especially during G2/M transition of mitosis in HCC. Additionally, immune infiltration analysis by CIBERSORTx revealed that mutilpe immune cells, including T_reg, etc., were significantly different in HCC samples with CENPF^high, compared with CENPF^low. These results collectively demonstrated that CENPF might serve as a potential prognostic biomarker and novel therapeutic target for HCC. However, further research is needed to validate our findings and promote the clinical application of CENPF in HCC.

SUBMITTER: Huang Y

PROVIDER: S-EPMC8040902 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHepatocellular carcinoma (HCC) is one of the deadliest tumors. The majority of HCC is detected in the late stage, and the clinical results for HCC patients are poor. There is an urgent need to discover early diagnostic biomarkers and potential therapeutic targets for HCC.MethodsThe GSE87630 and GSE112790 datasets from the Gene Expression Omnibus (GEO) database were downloaded to analyze the differentially expressed genes (DEGs) between HCC and normal tissues. R packages were used for Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses of the DEGs. A Search Tool for Retrieval of Interacting Genes (STRING) database was used to develop a protein-protein interaction (PPI) network, and also cytoHubba, Molecular Complex Detection (MCODE), EMBL-EBI, CCLE, Gene Expression Profiling Interactive Analysis (GEPIA), and Oncomine analyses were performed to identify hub genes. Gene expression was verified with a third GEO dataset, GSE25097. The Cancer Genome Atlas (TCGA) database was used to explore the correlations between the hub genes and clinical indexes of HCC patients. The functions of the hub genes were enriched by gene set enrichment analysis (GSEA), and the biological significance of the hub genes was explored by real-time polymerase chain reaction (qRT-PCR), western blot, immunofluorescence, CCK-8, colony formation, Transwell and flow cytometry assays with loss-of-function experiments in vitro.ResultsCentromere protein N (CENPN) was screened as a hub gene affecting HCC tumorigenesis. Evaluation by Cox regression showed that a high level of CENPN expression was an independent danger variable for poor prognosis of HCC. GSEA showed that high CENPN expression was linked to the following pathways: liver cancer subclass proliferation, cell cycle, p53 signaling pathway, Rb1 pathway, positive regulation of cell cycle G1/S phase transition, and DNA damage response signal transduction by p53 class moderators. Further cell experiments showed that knocking down CENPN expression decreased the proliferation and colony-forming abilities of HepG2 and Huh7 cells as well as Ki67 expression in these cell lines. The cell cycle was arrested in G1 phase, which is consistent with previous experiments on CENPN downregulation., but neither migration nor invasion were significantly affected. Western blot results revealed that the expression of p53, p27, p21, CDK4, cyclin D1, CDK2, cyclin E, pRb, E2F1 and c-myc decreased after CENPN knockdown, but there was no significant change in total Rb levels. In addition, CENPN-knockdown cells subjected to irradiation showed significantly enhanced of γ-H2AX expression and reduced colony formation.ConclusionCENPN functions as an oncogene in HCC and may be a therapeutic target and promising prognostic marker for HCC.

Project description:ObjectiveThe mechanisms of pseudouridine synthase (PUS) are not definite in hepatocellular carcinoma (HCC), the objective of this study is to investigate the effect of PUS genes in HCC.Materials and methodsDifferentially expressed and prognostic gene of PUS enzymes was identified based on The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and Gene Expression Profiling Interactive Analysis (GEPIA) databases. For the identified gene, pseudouridine synthase 1 (PUS1), was used for further research. The clinicopathological feature of PUS1 was analyzed by Student's t-test. Prognostic significance was explored by Kaplan-Meier (KM) analysis and Cox proportional hazards regression model. Receiver operating characteristic (ROC) curve was applied to appraise diagnostic and prognostic value. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) and Gene Set Enrichment Analysis (GSEA) were implemented to explore mechanism of PUS1. A Guangxi cohort was applied to verify differential expression. In vitro cell experiments were implemented to investigate the influence for proliferation, reactive oxygen species (ROS) level, migration, and invasion of HCC cells after a knockdown of PUS1.ResultsPUS1 was significantly overexpressed in HCC tissues, and patients with high PUS1 were related to unpromising clinicopathological features. Survival analysis revealed high PUS1 expression was associated with a poor overall survival (OS) and 1 year-recurrence free survival (RFS), was an independent risk factor. Meanwhile, ROC curve showed that PUS1 had a diagnostic and prognostic significance to HCC. Functional enrichment analysis implied that PUS1 may be involved in metabolic pathways, mitochondrial function, non-alcoholic fatty liver disease (NAFLD), and some important carcinogenic pathways. Cell assays revealed that knockdown of PUS1 significantly constrained the migration, proliferation, invasion and improved the ROS level of HCC cells.ConclusionPUS1 may be a prognostic biomarker and a underlying treatment target for HCC.

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Centromere Protein F (CENPF) Serves as a Potential Prognostic Biomarker and Target for Human Hepatocellular Carcinoma.

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