Identification of MCM family as potential therapeutic and prognostic targets for hepatocellular carcinoma based on bioinformatics and experiments

Yu, Lei; Wang, Shuhui; Liu, Jingmei; Yan, Wei; Han, Ping; Tian, Dean

doi:10.1016/j.lfs.2021.119227

Cited by 15 publications

(14 citation statements)

References 51 publications

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“…Hence, MCM6 not only interact with MCM2 to form a DNA replication license complex to directly activate DNA replication, but also interacts with DTL as well as ZWINT to accelerate the cell cycle. We also confirmed that MCM6 was significantly upregulated in HCC samples, which was in accordance with previous studies [ 28 , 29 ]. Moreover, we found that MCM6 can interact with Notch pathway to enhance the proliferation level in HCC cells.…”

Section: Discussionsupporting

confidence: 93%

MCM6 Promotes Hepatocellular Carcinoma Progression via the Notch Pathway: Clinical, Functional, and Genomic Insights

Hou

Zeng

Li³

et al. 2022

Computational and Mathematical Methods in Medicine

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Objective. To evaluate the expression profile of MCM6 in HCC and the relationship between MCM6 level and clinicopathological parameters through bioinformatics analysis of several databases. Methods. MCM expression level, clinical parameters, survival data, and gene set enrichment analysis were analyzed by bioinformatics database, including Oncomine™, UALCAN, HCCDB, TCGA, cBioPortal, and LinkedOmics. Real-time PCR, western blotting, and IHC staining were conducted to identify the expression of MCM6 in HCC compared to normal liver tissues. Results. Bioinformatics analysis indicated that the mRNA of MCM6 was obviously increased in multiple cancer types, especially in HCC. MCM6 level was positively associated with multiple clinical parameters (stage 3 and grades 3 and 4) and negatively associated with patient outcomes (overall survival). Moreover, enrichment of functions and signaling pathways analysis of MCM6 suggested that MCM6 might mediate DNA replication and cellular metabolism to promote the development and progression of HCC. Furthermore, IHC staining and western blotting indicated that the MCM6 was enhanced in HCC tissue, and MCM6 could promote HCC proliferation in activating Notch pathway via WB and bioinformatic analysis. Conclusion. This study actually revealed the expression and related functions of MCM6 in HCC. Furthermore, MCM6 is a carcinogenic role in activating Notch pathway to promote HCC cell proliferation, which may be a new prognostic biomarker and therapeutic target for HCC patients.

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Section: Discussionsupporting

confidence: 93%

MCM6 Promotes Hepatocellular Carcinoma Progression via the Notch Pathway: Clinical, Functional, and Genomic Insights

Hou

Zeng

Li³

et al. 2022

Computational and Mathematical Methods in Medicine

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“…Using GSEA, we also revealed that low CFHR4 expression was significantly associated with FCGR-activated reactions, the PLK1 pathway, reactant FCERI-mediated MAPK activation, the ATR pathway, the MCM pathway, the cascade reactions of PI3K and FGFR1, reactant-mediated MAPK activation and the FOXM1 pathway in patients. PLK1 ( 36 ), MAPK ( 37 ), ATR ( 38 ), MCM ( 39 ), PI3K and FGFR1 ( 40 ) have been shown to play increasingly crucial regulatory roles in HCC, and these studies and our results indicated that CFHR4 may inhibit the development and progression of HCC by regulating these signaling pathways. However, the association of CFHR4 with these signaling pathways was first discovered here, and the regulatory mechanisms require further exploration.…”

Section: Discussionsupporting

confidence: 63%

Identification of CFHR4 as a Potential Prognosis Biomarker Associated With lmmune Infiltrates in Hepatocellular Carcinoma

Wang²,

Ke³

et al. 2022

Front. Immunol.

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BackgroundComplement factor H-related 4 (CFHR4) is a protein-coding gene that plays an essential role in multiple diseases. However, the prognostic value of CFHR4 in hepatocellular carcinoma (HCC) is unknown.MethodsUsing multiple databases, we investigated CFHR4 expression levels in HCC and multiple cancers. The relationship between CFHR4 expression levels and clinicopathological variables was further analyzed. Various potential biological functions and regulatory pathways of CFHR4 in HCC were identified by performing a Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and Gene Set Enrichment Analysis (GSEA). Single-sample gene set enrichment analysis (ssGSEA) was performed to confirm the correlation between CFHR4 expression and immune cell infiltration. The correlations between CFHR4 expression levels in HCC and N6-methyladenosine (m6A) modifications and the competing endogenous RNA (ceRNA) regulatory networks were confirmed in TCGA cohort.ResultsCFHR4 expression levels were significantly decreased in HCC tissues. Low CFHR4 expression in HCC tissues was significantly correlated with the patients’ sex, race, age, TNM stage, pathological stage, tumor status, residual tumor, histologic grade and alpha fetal protein (AFP) level. GO and KEGG analyses revealed that differentially expressed genes related to CFHR4 may be involved in the synaptic membrane, transmembrane transporter complex, gated channel activity, chemical carcinogenesis, retinol metabolism, calcium signaling pathway, PPAR signaling pathway, insulin and gastric acid secretion. GSEA revealed that the FCGR-activated reaction, PLK1 pathway, ATR pathway, MCM pathway, cascade reactions of PI3K and FGFR1, reactant-mediated MAPK activation and FOXM1 pathway were significantly enriched in HCC with low CFHR4 expression. Moreover, CFHR4 expression was inversely correlated the levels of infiltrating Th2 cells, NK CD56bright cells and Tfh cells. In contrast, we observed positive correlations with the levels of infiltrating DCs, neutrophils, Th17 cells and mast cells. CFHR4 expression showed a strong correlation with various immunomarker groups in HCC. In addition, high CFHR4 expression significantly prolonged the overall survival (OS), disease-specific survival (DSS) and progression-free interval (PFI). We observed a substantial correlation between the expression of CFHR4 and multiple N6-methyladenosine genes in HCC and constructed potential CFHR4-related ceRNA regulatory networks.ConclusionsCFHR4 might be a potential therapeutic target for improving the HCC prognosis and is closely related to immune cell infiltration.

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“…MCM2 has been identified as a new biomarker for predicting tumor cell proliferation and prognosis of various cancers [ 18 , 19 ]. Although several recent studies with small sample size reported that MCM2 upregulated in HCC and promotes HCC cell proliferation [ 20 , 21 ], -lack of evidence elucidating the epigenetic mechanism regulating MCM2 expression in human HCC. In our present work, firstly, we comprehensively revealed and validated the expression profile of MCM2 in both clinical HCC samples and human hepatoma cell lines.…”

Section: Discussionmentioning

confidence: 99%

Demethylation at enhancer upregulates MCM2 and NUP37 expression predicting poor survival in hepatocellular carcinoma patients

et al. 2022

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Background Identification of novel biomarker is important for development of molecular-targeted therapy agents for patients with hepatocellular carcinoma (HCC). This study aims to identify potential prognostic biomarkers and investigate epigenetic mechanism of HCC development. Methods Public bulk-RNA seq datasets and proteomic dataset were screened for identification of potential prognostic biomarkers for HCC patients. Public methylomic datasets were analyzed for deciphering the epigenetic mechanism regulating HCC-associated gene expression. Immunoblotting, immunohistochemistry, real-time PCR, and pyrosequencing were used to validate the findings from bioinformatic analyses. Results Minichromosome maintenance complex component 2 (MCM2) and nucleoporin 37 (NUP37) were overexpressed in human HCC tissues and hepatoma cell lines. MCM2 significantly positively correlated with NUP37 expression. Higher expression of MCM2 or NUP37 was significantly associated with advanced tumor stage and worse overall survival in 3 large independent HCC cohorts (n = 820). MCM2 and NUP37 overexpression are independent prognostic risk factors for HCC patients. Demethylation at an enhancer of MCM2 gene was a common event in patients with HCC, which significantly negatively correlated with MCM2 and NUP37 mRNA expression. Conclusions Demethylation at enhancer regulates MCM2 and NUP37 expression in HCC. MCM2 and NUP37 are promising prognostic biomarkers and potential targets for epigenetic therapy in HCC patients.

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Identification of MCM family as potential therapeutic and prognostic targets for hepatocellular carcinoma based on bioinformatics and experiments

Cited by 15 publications

References 51 publications

MCM6 Promotes Hepatocellular Carcinoma Progression via the Notch Pathway: Clinical, Functional, and Genomic Insights

MCM6 Promotes Hepatocellular Carcinoma Progression via the Notch Pathway: Clinical, Functional, and Genomic Insights

Identification of CFHR4 as a Potential Prognosis Biomarker Associated With lmmune Infiltrates in Hepatocellular Carcinoma

Demethylation at enhancer upregulates MCM2 and NUP37 expression predicting poor survival in hepatocellular carcinoma patients

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