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Marker of proliferation Ki-67 (Ki-67) and minichromosome maintenance complex component 6 (MCM6) immunohistochemical staining. Moderate MCM6 labeling index in a case of grade 1endometroidcarcinoma (a, × 400 magnification). Strong staining for MCM6 in a grade 3 tumor (b, × 400). Low Ki-67 labeling index in grade 1 (c, × 400) and grade 3 (d, × 400) carcinoma samples. Expression of MCM6 sorted by histological grade (e) (p < 0.001) and FIGO stage (f) (p = 0.03). Expression of Ki-67, sorted by histological grades (g) (p < 0.001) and by FIGO (International Federation of Gynecology and Obstetrics) stage (h) (p = 0.06) (boxplots; Kruskal-Wallis tests)
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Minichromosome maintenance complex component 6 (MCM6) is involved in initiating DNA replication and is upregulated during licensed G0 phase of the cell cycle. This early expression permits its labeling of more proliferating cells than those by Ki-67. Here using a cohort of 89 endometrioid adenocarcinoma, we report findings made on the prognostic va...
Citations
... The minichromosome maintenance 6 (MCM6) functions as a regulator of DNA licensing, and plays a key role in cell cycle progression [133]. Overexpression of MCM6 may predict the unfavorable survival outcomes of patients with glioma [134], hepatocellular carcinoma (HCC) [135] and endometrioid endometrial adenocarcinoma [136]. Our meta-analysis identified that high expression of MCM6 was not associated with PFS of meningioma patients. ...
Meningioma is the most common primary brain tumor and many studies have evaluated numerous biomarkers for their prognostic value, often with inconsistent results. Currently, no reliable biomarkers are available to predict the survival, recurrence, and progression of meningioma patients in clinical practice. This study aims to evaluate the prognostic value of immunohistochemistry-based (IHC) biomarkers of meningioma patients. A systematic literature search was conducted up to November 2023 on PubMed, CENTRAL, CINAHL Plus, and Scopus databases. Two authors independently reviewed the identified relevant studies, extracted data, and assessed the risk of bias of the studies included. Meta-analyses were performed with the hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS), recurrence-free survival (RFS), and progression-free survival (PFS). The risk of bias in the included studies was evaluated using the Quality in Prognosis Studies (QUIPS) tool. A total of 100 studies with 16,745 patients were included in this review. As the promising markers to predict OS of meningioma patients, Ki-67/MIB-1 (HR = 1.03, 95%CI 1.02 to 1.05) was identified to associate with poor prognosis of the patients. Overexpression of cyclin A (HR = 4.91, 95%CI 1.38 to 17.44), topoisomerase II α (TOP2A) (HR = 4.90, 95%CI 2.96 to 8.12), p53 (HR = 2.40, 95%CI 1.73 to 3.34), vascular endothelial growth factor (VEGF) (HR = 1.61, 95%CI 1.36 to 1.90), and Ki-67 (HR = 1.33, 95%CI 1.21 to 1.46), were identified also as unfavorable prognostic biomarkers for poor RFS of meningioma patients. Conversely, positive progesterone receptor (PR) and p21 staining were associated with longer RFS and are considered biomarkers of favorable prognosis of meningioma patients (HR = 0.60, 95% CI 0.41 to 0.88 and HR = 1.89, 95%CI 1.11 to 3.20). Additionally, high expression of Ki-67 was identified as a prognosis biomarker for poor PFS of meningioma patients (HR = 1.02, 95%CI 1.00 to 1.04). Although only in single studies, KPNA2, CDK6, Cox-2, MCM7 and PCNA are proposed as additional markers with high expression that are related with poor prognosis of meningioma patients. In conclusion, the results of the meta-analysis demonstrated that PR, cyclin A, TOP2A, p21, p53, VEGF and Ki-67 are either positively or negatively associated with survival of meningioma patients and might be useful biomarkers to assess the prognosis.
... Definitive diagnosis of UCEC currently relies on histological examination. Successful diagnose and management can save patients from consequent morbidity and premature mortality [33]. Advances in detection mean that most patients with UCEC can be diagnosed or treated at an early stage, improving survival. ...
Uterine corpus endometrial carcinoma (UCEC) is one of the most common type of gynecological malignancies. Multiple lines of evidence indicated that CXC chemokines exerted an anti-tumor immunological role in the tumor microenvironment which were critical regulators of cancer immunity. However, the relevance of CXC chemokines in the evaluation of prognosis and immune infiltration of UCEC remains to be explored. This study utilized various online databases, including TCGA, UALCAN, Kaplan-Meier Plotter, cBioPortal, TIMER2.0, TISIDB, and MethSurv to perform the analysis. Gene expression data from the TCGA-UCEC dataset indicated decreased expression of CXCL2/12 and increased expression of CXCL14/17. CXCL2/12 expression was negatively whereas CXCL14/17 expression was positively correlated with clinicopathological features of UCEC patients, including cancer stage, patients’ age, weight and menopause status. Patients with higher CXCL12/14 expression corresponded with better clinical outcomes, which were not influenced by the genetic alterations. The differential expression of CXCL2/12/14/17 was not only significantly correlated with immune infiltration levels, but also the abundance of immune checkpoint inhibitors. Heatmaps of DNA methylation of CXCL2/12/14/17 were investigated, and 4 CpGs of CXCL2, 16 CpGs of CXCL12, 3 CpGs of CXCL14/17 were identified where altered methylation affected the prognosis of UCEC patients. These findings provided novel insights into the immunologic features of UCEC and might pave the way toward the prognostic evaluation and immunotherapy selection based on CXCL2/12/14/17 expression status.
... Clinical and histological data are summarized in our previous publication [13]. Mean age at diagnosis was 66.8 ± 11.0 years. ...
... The expression levels of MCM6 and Ki67 were previously published by our team [13]. Cytoplasmic expression of HuR was strongly correlated with the expression levels of MCM6 (rho = 0.59 and p < 0.001) and Ki67 (rho = 0.49 and p < 0.001). ...
... In our study, cytoplasmic expression of HuR was strongly correlated with the expression levels of two markers of proliferation, MCM6 and Ki67. These data are concordant with our previous studies showing the prognostic value of the proliferation markers MCM6 and Ki-67 in endometrial adenocarcinoma [13], lung cancer [11], and meningioma [23]. ...
HuR regulates cytoplasmic mRNA stability and translatability, with its expression correlating with adverse outcomes in various cancers. This study aimed to assess the prognostic value and pro-oncogenic properties of HuR and its post-translational isoforms methyl-HuR and phospho-HuR in endometrial adenocarcinoma. Examining 89 endometrioid adenocarcinomas, we analyzed the relationship between HuR nuclear or cytoplasmic immunostaining, tumor-cell proliferation, and patient survival. HuR cytoplasmic expression was significantly increased in grade 3 vs. grade 1 adenocarcinomas (p < 0.001), correlating with worse overall survival (OS) (p = 0.02). Methyl-HuR cytoplasmic expression significantly decreased in grade 3 vs. grade 1 adenocarcinomas (p < 0.001) and correlated with better OS (p = 0.002). Phospho-HuR nuclear expression significantly decreased in grade 3 vs. grade 1 adenocarcinomas (p < 0.001) and non-significantly correlated with increased OS (p = 0.06). Cytoplasmic HuR expression strongly correlated with proliferation markers MCM6 (rho = 0.59 and p < 0.001) and Ki67 (rho = 0.49 and p < 0.001). Conversely, these latter inversely correlated with cytoplasmic methyl-HuR and nuclear phospho-HuR. Cytoplasmic HuR expression is a poor prognosis marker in endometrioid endometrial adenocarcinoma, while cytoplasmic methyl-HuR and nuclear phosphoHuR expressions are markers of better prognosis. This study highlights HuR as a promising potential therapeutic target, especially in treatment-resistant tumors, though further research is needed to understand the mechanisms regulating HuR subcellular localization and post-translational modifications.
... While the role of MCM6 in developmental disease is unknown, it does have a well-described role in tumorigenesis (Mughal et al. 2019). A number of studies have shown increased expression of MCM6 in malignant tumors, such as meningiomas, non-small cell lung carcinoma, chondrosarcoma, endometrial adenocarcinoma and colorectal cancer (Shim et al. 2021;Jia et al. 2020;Issac et al. 2019;Cai et al. 2018;Gauchotte et al. 2012;Hotton et al. 2018). High MCM6 expression is associated with tumor invasion and the development of metastasis via enhanced tumor cell proliferation rates Li et al. 2020). ...
The minichromosome maintenance (MCM) complex acts as a DNA helicase during DNA replication, and thereby regulates cell cycle progression and proliferation. In addition, MCM-complex components localize to centrosomes and play an independent role in ciliogenesis. Pathogenic variants in genes coding for MCM components and other DNA replication factors have been linked to growth and developmental disorders as Meier–Gorlin syndrome and Seckel syndrome. Trio exome/genome sequencing identified the same de novo MCM6 missense variant p.(Cys158Tyr) in two unrelated individuals that presented with overlapping phenotypes consisting of intra-uterine growth retardation, short stature, congenital microcephaly, endocrine features, developmental delay and urogenital anomalies. The identified variant affects a zinc binding cysteine in the MCM6 zinc finger signature. This domain, and specifically cysteine residues, are essential for MCM-complex dimerization and the induction of helicase activity, suggesting a deleterious effect of this variant on DNA replication. Fibroblasts derived from the two affected individuals showed defects both in ciliogenesis and cell proliferation. We additionally traced three unrelated individuals with de novo MCM6 variants in the oligonucleotide binding (OB)-fold domain, presenting with variable (neuro)developmental features including autism spectrum disorder, developmental delay, and epilepsy. Taken together, our findings implicate de novo MCM6 variants in neurodevelopmental disorders. The clinical features and functional defects related to the zinc binding residue resemble those observed in syndromes related to other MCM components and DNA replication factors, while de novo OB-fold domain missense variants may be associated with more variable neurodevelopmental phenotypes. These data encourage consideration of MCM6 variants in the diagnostic arsenal of NDD.
... Among others proliferation markers, the mini-chromosome maintenance (MCM) proteins as the key proteins in the initiation of DNA synthesis and DNA replication, are considered to be linked with histological grades in various neoplastic development [31]. A recent report indicates that MCM is associated with histological grade and survival ability of cells in endometrioid endometrial adenocarcinoma, which may be a new marker in early diagnosis [15]. In our study, we verify that SNHG16 accelerates NPC progression by acting as a sponge of miR-23b-3p and activating MCM6 indirectly, which may provide a new insight for NPC prediction or prognosis. ...
This study aims to investigate the mechanism of tumor-derived exosomal (EVs) SNHG16 in promoting the progression of nasopharyngeal carcinoma (NPC). QRT-PCR was used to detect the expression of SNHG16, miR-23b-5p and MCM6 in NPC. MTT, flow cytometry and transwell were used to detect the effects of them on the proliferation, cycle, apoptosis and invasion ability of NPC. Transmission electron microscopy, Western blotting and BCA were used to verify the regulation of exosome secretion under different oxygen environments. Our results showed that hypoxia induces tumor-derived exosome SNHG16 to mediate NPC progression through the miR-23b-5p/MCM6 pathway.
... 215 Upregulation of MCM6 also exists in non-small cell lung cancer and breast cancer with worse survival and higher histological grade. [216][217][218] The reasons for abnormal MCMs expression remain unclear. There are two possible speculations: (a) CDK-mediated MCM complex dissociating prevents DNA re-replication. ...
Accurate and integral cellular DNA replication is modulated by multiple replication‐associated proteins, which is fundamental to preserve genome stability. Furthermore, replication proteins cooperate with multiple DNA damage factors to deal with replication stress through mechanisms beyond their role in replication. Cancer cells with chronic replication stress exhibit aberrant DNA replication and DNA damage response, providing an exploitable therapeutic target in tumors. Numerous evidence has indicated that posttranslational modifications (PTMs) of replication proteins present distinct functions in DNA replication and respond to replication stress. In addition, abundant replication proteins are involved in tumorigenesis and development, which act as diagnostic and prognostic biomarkers in some tumors, implying these proteins act as therapeutic targets in clinical. Replication‐target cancer therapy emerges as the times require. In this context, we outline the current investigation of the DNA replication mechanism, and simultaneously enumerate the aberrant expression of replication proteins as hallmark for various diseases, revealing their therapeutic potential for target therapy. Meanwhile, we also discuss current observations that the novel PTM of replication proteins in response to replication stress, which seems to be a promising strategy to eliminate diseases. Accurate DNA replication is modulated by multiple replication‐associated proteins, which is fundamental to preserve genome stability. Abundant replication proteins are involved in tumorigenesis and development, implying these proteins act as therapeutic targets in clinical. Replication‐target cancer therapy emerges as the times require. Furthermore, the novel posttranslational modification of replication proteins in response to replication stress, which seems to be a promising strategy to eliminate diseases.
... It functions by unwinding the two DNA spiral strands [9] and by promoting G1/S transition [10]. Many studies have shown that the level of expression of MCM6, basing on mRNA detection or immunohistochemistry, was correlated with clinical outcome, e.g., in gliomas, renal cell carcinoma, endometrial adenocarcinoma, lung cancer, osteosarcoma, pheochromocytoma, neuroblastoma, and meningioma [4,[10][11][12][13][14][15][16][17][18][19][20]. Our previous evidence singled out MCM6 as an efficient marker by virtue of its dominant presence in proliferating cells that resulted in striking clear-cut differences in MCM6 labeling index (LI) of the indolent vs. the recurrent meningiomas, with a high reproducibility [4]. ...
Simple Summary
The aim of this study was to evaluate the prognostic value of MCM6 relative to that of Ki-67 in a series of grade 1 (World Health Organization 2021; n = 100) and grade 2 (atypical) meningiomas (n = 69), using immunohistochemistry, and to evaluate its correlation with methylation classes. In a multivariate model, the LI (Labeling Index) of MCM6 correlated with progression free survival of grade 2, but not grade 1 meningiomas. MCM6 was also correlated with overall survival in univariate analysis. No correlation was found with the methylation classes and subclasses returned by the meningioma algorithm MNGv2.4. We found a significant correlation between PTEN loss and high MCM6 or Ki-67 LI. Our evidence here suggests that MCM6 is a relevant and reproducible marker in atypical meningiomas. It is also easy-to use and could also allow to identify a highly aggressive subtype of proliferative meningiomas.
Abstract
The aim of this study was to evaluate the prognostic value of MCM6, in comparison with Ki-67, in two series of grade 1 and 2 meningiomas, and to evaluate its correlation with methylation classes. The first cohort included 100 benign (grade 1, World Health Organization 2021) meningiomas, and the second 69 atypical meningiomas (grade 2). Immunohistochemical Ki-67 and MCM6 labeling indices (LI) were evaluated independently by two observers. Among the atypical meningiomas, 33 cases were also studied by genome-wide DNA methylation. In grade 2 meningiomas, but not grade 1, both Ki-67 and MCM6 LIs were correlated with PFS (p = 0.004 and p = 0.005, respectively; Cox univariate analyses). Additionally, MCM6 was correlated with overall survival only in univariate analysis. In a multivariate model, including mitotic index, Ki-67, MCM6, age, sex, and the quality of surgical resection, only MCM6 was correlated with PFS (p = 0.046). Additionally, we found a significant correlation between PTEN loss and high MCM6 or Ki-67 LIs. Although no correlation was found with the methylation classes and subtypes returned by the meningioma algorithm MNGv2.4., MCM6 LI was significantly correlated with the methylation of 2 MCM6 gene body loci. In conclusion, MCM6 is a relevant prognostic marker in atypical meningiomas. This reproducible and easy-to-use marker allows the identification of a highly aggressive subtype of proliferative meningiomas, characterized notably by frequent PTEN losses, which was previously reported to be sensitive to histone deacetylase inhibitors.
... It has been recently assumed that MCM6 may represent a protein that can be linked with the development of multiple cancer types 53 . Moreover, MCM6 overexpression may predict the poor survival of patients with one of many cancer types, such as glioma 54 , hepatocellular carcinoma 55 and endometrioid endometrial adenocarcinoma 56 . As a member of the double-strand break repair pathway (GO:0000727), MCM6 protein exhibited considerable upregulation in SDS-exposed HaCaT keratinocytes upon our experimental design. ...
There is no direct evidence supporting that SDS is a carcinogen, so to investigate this fact, we used HaCaT keratinocytes as a model of human epidermal cells. To reveal the candidate proteins and/or pathways characterizing the SDS impact on HaCaT, we proposed comparative proteoinformatics pipeline. For protein extraction, the performance of two sample preparation protocols was assessed: 0.2% SDS-based solubilization combined with the 1DE-gel concentration (Protocol 1) and osmotic shock (Protocol 2). As a result, in SDS-exposed HaCaT cells, Protocol 1 revealed 54 differentially expressed proteins (DEPs) involved in the disease of cellular proliferation (DOID:14566), whereas Protocol 2 found 45 DEPs of the same disease ID. The ‘skin cancer’ term was a single significant COSMIC term for Protocol 1 DEPs, including those involved in double-strand break repair pathway (BIR, GO:0000727). Considerable upregulation of BIR-associated proteins MCM3, MCM6, and MCM7 was detected. The eightfold increase in MCM6 level was verified by reverse transcription qPCR. Thus, Protocol 1 demonstrated high effectiveness in terms of the total number and sensitivity of MS identifications in HaCaT cell line proteomic analysis. The utility of Protocol 1 was confirmed by the revealed upregulation of cancer-associated MCM6 in HaCaT keratinocytes induced by non-toxic concentration of SDS. Data are available via ProteomeXchange with identifier PXD035202.
... Patients with a high level of MCM6 were found to have poorer survival and a higher risk of death in craniopharyngioma, non-small cell lung cancer, and mantle cell lymphoma (40)(41)(42). High MCM6 level is also associated with a higher histological grade in breast cancer, low-grade chondrosarcoma and endometrioid endometrial adenocarcinoma (40,43). MCM7 is up-regulated in lung adenocarcinoma and is associated with poor prognosis (44). ...
... Patients with a high level of MCM6 were found to have poorer survival and a higher risk of death in craniopharyngioma, non-small cell lung cancer, and mantle cell lymphoma (40)(41)(42). High MCM6 level is also associated with a higher histological grade in breast cancer, low-grade chondrosarcoma and endometrioid endometrial adenocarcinoma (40,43). MCM7 is up-regulated in lung adenocarcinoma and is associated with poor prognosis (44). ...
Background
Clear cell renal cell carcinoma (ccRCC) accounts for 60-70% of renal cell carcinoma (RCC) cases. Finding more therapeutic targets for advanced ccRCC is an urgent mission. The minichromosome maintenance proteins 2-7 (MCM2-7) protein forms a stable heterohexamer and plays an important role in DNA replication in eukaryotic cells. In the study, we provide a comprehensive study of MCM2-7 genes expression and their potential roles in ccRCC.
Methods
The expression and prognosis of the MCM2-7 genes in ccRCC were analyzed using data from TCGA, GEO and ArrayExpress. MCM2-7 related genes were identified by weighted co-expression network analysis (WGCNA) and Metascape. CancerSEA and GSEA were used to analyze the function of MCM2–7 genes in ccRCC. The gene effect scores (CERES) of MCM2-7, which reflects carcinogenic or tumor suppressor, were obtained from DepMap. We used clinical and expression data of MCM2-7 from the TCGA dataset and the LASSO Cox regression analysis to develop a risk score to predict survival of patients with ccRCC. The correlations between risk score and other clinical indicators such as gender, age and stage were also analyzed. Further validation of this risk score was engaged in another cohort, E-MTAB-1980 from the ArrayExpress dataset.
Results
The mRNA and protein expression of MCM2-7 were increased in ccRCC compared with normal tissues. High MCM2, MCM4, MCM6 and MCM7 expression were associated with a poor prognosis of ccRCC patients. Functional enrichment analysis revealed that MCM2-7 might influence the progress of ccRCC by regulating the cell cycle. Knockdown of MCM7 can inhibit the proliferation of ccRCC cells. A two-gene risk score including MCM4 and MCM6 can predict overall survival (OS) of ccRCC patients. The risk score was successfully verified by further using Arrayexpress cohort.
Conclusion
We analyze MCM2-7 mRNA and protein levels in ccRCC. MCM7 is determined to promote tumor proliferation. Meanwhile, our study has determined a risk score model composed of MCM2-7 can predict the prognosis of ccRCC patients, which may help future treatment strategies.
... Furthermore, MCM pro-teins are expressed more in malignant cells than in normal cells. MCM6 expression has been evaluated in various human cancers and has been found associated with tumor cell proliferation, invasion, and metastasis [9][10][11][12][13][14][15]. However, its prognostic role in mesenchymal neoplasms has not yet been investigated. ...
... The increase or inhibition of MCM protein expression results in genomic instability, which could lead to carcinogenesis [22]. Upregulation of MCM6 has been evaluated in and been shown to have prognostic value for various human carcinomas, such as endometrial adenocarcinoma, non-small lung cancer, hepatocellular carcinoma, breast cancer, pancreatic adenocarcinoma, meningioma, and colorectal cancer [7][8][9][10][11][12]14]. However, studies on MCM proteins, including MCM6, in soft tissue tumors are limited. ...
Minichromosome maintenance (MCM) proteins are essential for the initiation of DNA replication and they are prognostic markers in various human cancers. The aim of this study was to investigate the role of the MCM6 protein in gastrointestinal stromal tumor (GIST) and its clinical and prognostic significance. We evaluated MCM6 expression in 211 GIST samples using immunohistochemistry. We used the receiver operating characteristic curve (ROC) to identify optimal cut-off values. High MCM6 expression was associated with tumor size, mitosis, tumor necrosis, presence of recurrence/metastasis, and the National Institute of Health (NIH) and Armed Forces Institute of Pathology (AFIP) malignant risk criteria. Patients with high MCM6 expression had significantly shorter overall survival (OS) and disease-free survival (DFS) than those with low MCM6 expression. Univariate analysis indicated that tumor size, mitosis, AFIP and NIH malignant risk criteria, and high MCM6 expression were significantly associated with poor OS and DFS. High MCM6 expression and high-risk group categorization based on the NIH criteria were independent prognostic factors for OS and DFS. High MCM6 expression is significantly associated with tumor progression and aggressiveness and is an independent factor for shorter survival in GIST patients. MCM6 expression could be a predictive biomarker for tumor aggressiveness as well as a treatment target.
