MCM2, MCM4, and MCM6 in Breast Cancer: Clinical Utility in Diagnosis and Prognosis

Issac, Marianne Samir M.; Yousef, Einas; Tahir, Muhammad; Gaboury, Louis

doi:10.1016/j.neo.2019.07.011

Cited by 86 publications

(80 citation statements)

References 61 publications

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“…MCM6, a component of minichromosome maintenance (MCM) protein complex, functions to initiate DNA replication and unwinding based on its replicative helicase activity. It has been demonstrated that the overexpression of MCM6 can promote tumorigenesis, [ 31 ] also seen in the present study. Further study is needed to identify how DNA methylation regulated MCM6 expression to affect the development of RB.…”

Section: Discussionsupporting

confidence: 88%

Bioinformatics analysis of multi-omics data identifying molecular biomarker candidates and epigenetically regulatory targets associated with retinoblastoma

Zeng¹,

He²,

Liu³

et al. 2020

Medicine

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Retinoblastoma (RB) is the commonest malignant tumor of the infant retina. Besides genetic changes, epigenetic events are also considered to implicate the occurrence of RB. This study aimed to identify significantly altered protein-coding genes, DNA methylation, microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and their molecular functions and pathways associated with RB, and investigate the epigenetically regulatory mechanism of DNA methylation modification and non-coding RNAs on key genes of RB via bioinformatics method. We obtained multi-omics data on protein-coding genes, DNA methylation, miRNAs, and lncRNAs from the Gene Expression Omnibus database. We identified differentially expressed genes (DEGs) using the Limma package in R, discerned their biological functions and pathways using enrichment analysis, and conducted the modular analysis based on protein-protein interaction network to identify hub genes of RB. Survival analyses based on The Cancer Genome Atlas clinical database were performed to analyze prognostic values of key genes of RB. Subsequently, we identified the differentially methylated genes, differentially expressed miRNAs (DEMs) and lncRNAs (DELs), and intersected them with key genes to analyze possible targets of the underlying epigenetic regulatory mechanisms. Finally, the ceRNA network of lncRNAs-miRNAs-mRNAs was constructed using Cytoscape. A total of 193 DEGs, 74 differentially methylated-DEGs (DM-DEGs), 45 DEMs, 5 DELs were identified. The molecular pathways of DEGs were enriched in cell cycle, p53 signaling pathway, and DNA replication. A total of 10 key genes were identified and found significantly associated with poor survival outcome based on survival analyses, including CDK1, BUB1, CCNB2, TOP2A, CCNB1, RRM2, KIF11, KIF20A, NDC80, and TTK. We further found that hub genes MCM6 and KIF14 were differentially methylated, key gene RRM2 was targeted by DEMs, and key genes TTK, RRM2, and CDK1 were indirectly regulated by DELs. Additionally, the ceRNA network with 222 regulatory associations was constructed to visualize the correlations between lncRNAs-miRNAs-mRNAs. This study presents an integrated bioinformatics analysis of genetic and epigenetic changes that may be associated with the development of RB. Findings may yield many new insights into the molecular biomarker candidates and epigenetically regulatory targets of RB.

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Section: Discussionsupporting

confidence: 88%

Bioinformatics analysis of multi-omics data identifying molecular biomarker candidates and epigenetically regulatory targets associated with retinoblastoma

Zeng¹,

He²,

Liu³

et al. 2020

Medicine

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“…Interestingly, CHEK1 was co-expressed with minichromosome maintenance complex component (MCM family) and flap eendonuclease 1 (FEN1) expressed in colorectal cancer. The MCM family (MCMs) has been reported to be associated with numerous cancer types [35][36][37], such as the promotion of metastasis of liver cancer through the Mitogen-activated protein kinase kinase(MEK)/ extracellular signal-regulated kinases (ERK) pathway (MCM6) [38], as a prognostic factor in patients with lung squamous cell carcinoma [39]. Many studies indicate the central roles of MCMs in genome stability, including the regulation of transcription, chromatin remodeling, and checkpoint responses [40][41][42].…”

Section: Co-expression Profile Of Chek1 In Colorectal Cancermentioning

confidence: 99%

Gene Expression Alterations and Molecular Analysis of CHEK1 in Solid Tumors

Fadaka

Bakare

Sibuyi

et al. 2020

Cancers

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Alterations in the Checkpoint kinase (CHEK1) gene, its regulation, and the possible clinical outcomes in human solid tumors have not been previously examined. Therefore, the present study was carried out to evaluate the expression of CHEK1 in solid tumors as well as the mechanism by which it can be regulated through non-coding RNAs. The expression of CHEK1 was investigated using Oncomine analysis. cBioPortal, Kaplan–Meier Plotter, and PrognoScan were performed to identify the prognostic roles of this gene in solid tumors. The copy number alteration, mutation, interactive analysis, and visualization of the altered networks were performed by cBioPortal. The molecular binding analysis was carried out by Schrodinger suite, PATCHDOCK, and discovery studio visualizer. The study demonstrated that the CHEK1 gene was differentially expressed in four different cancers, and that reduced CHEK1 mRNA expression is an unfavorable prognostic factor for patients with gastric and colorectal cancer. The molecular docking results showed that the CHEK1 gene can be regulated by microRNAs (miR-195-5p) due to the number of stable hydrogen atoms observed within the distance of 2.0 Å and the favorable amino acids (Ala221, Ile353, Ile365, Ile756, Val797, Val70, Val154, Ile159, Val347, Tyr804, Phe811, Tyr815, and Phe156) identified in the binding pocket of the argonaute protein. Due to the possibility of CHEK1’s involvement in solid tumors, it may potentially be a target for therapeutic intervention in cancer. Further studies into the interaction between CHEK1 and other co-expressed genes may give further insight into other modes of regulation of this gene in cancer patients.

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“…Besides, extent of HMGA1 phosphorylation has been found to be differentially expressed in response to MCM2 perturbation and has a significant role to play in modulating cell behaviors of lung cancer cells [ 17 ]. MCM2 also has wide clinical application value in breast cancer diagnosis and prognosis [ 18 ]. Of note, MCM2 has been proved to be closely related to stem cells.…”

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: NF-κB maintains the stemness of colon cancer cells by downregulating miR-195-5p/497–5p and upregulating MCM2

Wang

Guo²,

Zhou

et al. 2020

J Exp Clin Cancer Res

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Background Colon cancer represents one of the leading causes of gastrointestinal tumors in industrialized countries, and its incidence appears to be increasing at an alarming rate. Accumulating evidence has unveiled the contributory roles of cancer stem cells (CSCs) in tumorigenicity, recurrence, and metastases. The functions of NF-kappa B (NF-κB) activation on cancer cell survival, including colon cancer cells have encouraged us to study the role of NF-κB in the maintenance of CSCs in colon cancer. Methods Tumor samples and matched normal samples were obtained from 35 colon cancer cases. CSCs were isolated from human colon cancer cell lines, where the stemness of the cells was evaluated by cell viability, colony-forming, spheroid-forming, invasion, migration, and apoptosis assays. NF-κB activation was then performed in subcutaneous tumor models of CSCs by injecting lipopolysaccharides (LPS) i.p. Results We found that NF-κB activation could reduce the expression of miR-195-5p and miR-497-5p, where these two miRNAs were determined to be downregulated in colon cancer tissues, cultured colon CSCs, and LPS-injected subcutaneous tumor models. Elevation of miR-195-5p and miR-497-5p levels by their specific mimic could ablate the effects of NF-κB on the stemness of colon cancer cells in vivo and in vitro, suggesting that NF-κB could maintain the stemness of colon cancer cells by downregulating miR-195-5p/497–5p. MCM2 was validated as the target gene of miR-195-5p and miR-497-5p in cultured colon CSCs. Overexpression of MCM2 was shown to restore the stemness of colon cancer cells in the presence of miR-195-5p and miR-497-5p, suggesting that miR-195-5p and miR-497-5p could impair the stemness of colon cancer cells by targeting MCM2 in vivo and in vitro. Conclusions Our work demonstrates that the restoration of miR-195-5p and miR-497-5p may be a therapeutic strategy for colon cancer treatment in relation to NF-κB activation.

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MCM2, MCM4, and MCM6 in Breast Cancer: Clinical Utility in Diagnosis and Prognosis

Cited by 86 publications

References 61 publications

Bioinformatics analysis of multi-omics data identifying molecular biomarker candidates and epigenetically regulatory targets associated with retinoblastoma

Bioinformatics analysis of multi-omics data identifying molecular biomarker candidates and epigenetically regulatory targets associated with retinoblastoma

Gene Expression Alterations and Molecular Analysis of CHEK1 in Solid Tumors

RETRACTED ARTICLE: NF-κB maintains the stemness of colon cancer cells by downregulating miR-195-5p/497–5p and upregulating MCM2

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