MCM7 (minichromosome maintenance complex component 7)

2020-09-01   Keli Lima , Eduardo Magalhães Rego , Joao Agostinho Machado-Neto 

Identity

HGNC
LOCATION
7q22.1
LOCUSID
ALIAS
CDC47,MCM2,P1.1-MCM3,P1CDC47,P85MCM,PNAS146,PPP1R104
FUSION GENES

Abstract

MCM7 belongs to the minichromosome maintenance (MCM) protein family, which compromises DNA helicases that play a key role in DNA replication and G1\/S cell cycle progression. There are plenty of studies on MCM7 expression for cancer development and progression. Increased levels of MCM7 are consistently implicated in high aggressiveness characteristics and poor clinical outcomes in several cancer types. In the present review, the data on DNA\/RNA, the protein encoded, and the implication of MCM7 as diagnostic, prognostic, and biological values in cancer are described.

DNA/RNA

Description

The entire MCM7 gene is approximately 9.2 Kb (start: 100092728 and end: 100101940 bp; orientation: reverse strand). In the NCBI database (https://www.ncbi.nlm.nih.gov/gene), there are 3 transcript variants for CDC7 that encode for the 2 protein isoforms. The transcript variant 1 (transcript length: 2467 bp); encodes the longer protein, isoform 1 (719 aa). The transcript variant 2 (transcript length: 2996 bp) and 3 (transcript length: 2542 bp) encodes the short protein, isoform 2 (543 aa). Both transcript variants, 2 and 3, contain an additional internal segment that leads to translation initiation from an in-frame downstream AUG compared to transcript variant 1, which leads to a shorter N-terminus. In Ensembl database (http://www.ensembl.org/), there are ten additional transcript variants for MCM7, two are protein coding transcripts (ENST00000343023.10: 1968 bp and 389 aa, and ENST00000425308.5: 1497 bp and 183 aa), one is a nonsense-mediated mRNA decay (ENST00000491245.6: 648 bp and 83 aa) and seven are non-protein-coding transcripts.

Proteins

Atlas Image
Figure 1. Schematic MCM7 protein structure. (A) MCM7 protein presents two isoforms (isoform 1: 719 aa, isoform 2: 543 aa) and contains a minichromosome maintenance (MCM) domain. The position of amino acids (aa) is indicated in the Figure. The 3D reconstitution of the isoform 1 of MCM7 protein was constructed using the Swiss-model platform (https://swissmodel.expasy.org/), and cartoon (B) and surface (C) versions of the protein are illustrated.

Description

Two MCM7 isoforms are better described: the isoform 1 consists of 719 amino acids (aa), while isoform 2 consists of 543 aa, both isoforms present a conserved MCM domain in the C-terminal region. The schematic representation of the MCM7 isoforms are illustrated in Figure 1.

Expression

Ubiquitous.

Localisation

Cytoplasm and nucleus. The nuclear import of MCM proteins occurs as a complex.

Function

MCM7 belongs to the minichromosome maintenance (MCM) protein family, which compromises DNA helicases important for initiating DNA replication and for cell cycle progression (Forsburg, 2008; Lo Sardo et al., 2017). This protein family consists of at least six members (MCM2-7) that have been implicated in the regulatory machinery to ensure DNA synthesis happens once per cell cycle. During the G1 phase of the cell cycle, the MCM complex is inactive around the double DNA strand at the replication origins. In the S phase of the cell cycle, there is the recruitment of helicase cofactors, CDC45 and GINS, for the MCM complex (forming the CMG complex) that activates its activity, translocating it in the 3 to 5 direction along the DNA enabling the replisome assembly. The head-to-head configuration of the MCM complexes provides bidirectional DNA synthesis (Hyrien, 2016). Although uncomplexed MCM7 did not present ATPase or DNA helicase activity, it plays an essential for DNA helicase activity of the MCM complex (Figure 2). MCM7 expression is regulated by E2F transcription factors under growth factor stimulation by PI3K/AKT/ GSK3B / CCND1 / RB1 axis (Ishimi, 2018; Suzuki et al., 1998; Yoshida and Inoue, 2004). MCM7 is a marker of cell proliferation and its aberrant expression contributes to tumor development and progression (Honeycutt et al., 2006).
Atlas Image
Figure 2. Model for MCM7 function in DNA replication. MCM7 is a component of minichromosome maintenance (MCM) complex (MCM2-7), forming a hexameric ring that binds to DNA and acts as a replication licensing. The recruitment of CDC45 and GINS is required for helicase activity of the complex (CMG complex). Upon DNA unwinding, occurs the formation of replication forks in the double stranded DNA at origin and DNA synthesis by the recruitment of DNA polymerases.

Homology

MCM7 has high homology among different species (Table 1).
Table 1. Comparative identity of human MCM7 with other species
% Identity for: Homo sapiens BIRC7SymbolProteinDNA
vs. P. troglodytesMCM7 99.9 99.4
vs. M. mulattaMCM7 98.4 96.4
vs. C. lupus MCM7 96.2 88.7
vs. B. taurus MCM7 96.4 89.3
vs. M. musculus Mcm7 92.8 86.9
vs. R. norvegicus Mcm7 94.3 87.1
vs. X. tropicalis mcm7 84.8 74.1
vs. D. rerio mcm7 80.8 73.6
vs. D. melanogaster Mcm7 67.5 63.7
vs. A. gambiae AgaP_AGAP005800 67.0 64.2
vs. C. elegans mcm-7 52.5 54.6
vs. S. cerevisiae MCM7 50.1 51.2
vs. K. lactis KLLA0E23189g 52.2 52.1
vs. E. gossypii AGOS_ADR041W 50.7 54.0
vs. S. pombe mcm7 50.8 51.7
vs. M. oryzae MGG_09300 50.8 54.6
vs. N. crassa NCU08119 52.4 56.4
vs. A. thaliana PRL 52.4 53.7
vs. O. sativa Os12g0560700 50.9 53.1

(Source: http://www.ncbi.nlm.nih.gov/homologene)

Mutations

Somatic

Recurrent mutations in the MCM7 gene are rare. A total of 596 out of 47005 (1.3%) tested samples presented MCM7 genetic alterations (mutations, amplifications, deep deletions, and multiple alterations), as reported on cBioPortal (http://www.cbioportal.org). A total of 218 somatic mutations (0.5% of the samples) was found: 170 missense substitutions, 42 truncating, 4 inframe, and 2 other mutations. In COSMIC (Catalogue of Somatic Mutations in Cancer; http://cancer.sanger.ac.uk/cancergenome/projects/cosmic) data base, a total of 465 (1.2%) unique samples presenting MCM7 mutations were found among the 37667 samples tested, being 200 missense substitutions, 81 synonymous substitutions, 28 nonsense substitutions, 11 frameshift deletions, 3 frameshift insertions, 2 inframe deletions and 1 inframe insertion, and 60 other mutations.

Implicated in

Entity name
Adrenocortical carcinomas
Note
MCM7 was identified as a potential diagnosis marker for distinguishing benign tumors from malignant adrenocortical tumors (Aporowicz et al., 2019).
Garbicz and colleagues (Garbicz et al., 2017) reported a significant increase of MCM7 expression in ACTHomas. In addition, MCM7 was ubiquitously overexpressed in Crooke cell adenomas and a combination of MCM7 and MIR106B - MIR25 expressions accurately differentiated invasive from non-invasive tumors and predicted postoperative tumor recurrence/progression.
Entity name
Bladder cancer
Note
Atypical inverted papilloma presented increased MCM7 levels compared to typical papilloma, which was associated with higher proliferative activity induced by HPV infection. In addition, MCM7 expression was observed predominantly in the nucleus and, to a lesser extent, weakly in the cytoplasm (Shigehara et al., 2011a). In another study, the authors reported that the MCM7 expression in normal bladder mucous or HPV-negative bladder tissues was lower compared to HPV-positive tumors (Shigehara et al., 2011b). In a papillomavirus-associated bladder carcinoma case study, it was shown that MCM7 was highly expressed both in the basal cells of the condyloma tissue and in the basal layer of the tumor tissues (Kawaguchi et al., 2012). In a multicenter bladder cancer cohort (576 patients), MCM7 expression was an independent prognostic factor for disease progression (Fristrup et al., 2013).
Higher MCM7 expression was found in T24R2, a cisplatin-resistant bladder cancer cell line compared to T24, a cisplatin-sensitive bladder cancer cell line, suggesting a potential role for MCM7 in chemoresistance (Kim et al., 2016).
Entity name
Breast cancer
Note
The expression of MCM7 was significantly higher in tumor than in adjacent non-tumor tissues, suggesting a potential role for this protein in the tumor development and progression (Lu et al., 2011; Song et al., 2006). In MCF-7 breast cancer cells, MCM7 participates in the MYB network and it was up-regulated by exposure to estradiol (Wu et al., 2012). Treatment with cantharidin inhibits the expression of MCM7, reducing cell proliferation, in MCF-7 cells (Zhang and Yan, 2015). In addition, the downregulation of MCM7 upregulated γH2AX (phosphorylated H2AX) in tamoxifen-resistant MCF7 and T47D breast cells (Liang et al., 2017).
Entity name
Cervical cancer
Note
MCM7 interacts with E6 viral protein from HPV, which may be implicated in chromosomal abnormalities and cell transformation (Kukimoto et al., 1998). In cervical lesions associated with HPV-16, MCM7 expression was higher in intraepithelial lesions, and the highest levels were observed in cancer (Brake et al., 2003). Similarly, the expression of MCM7 presented a predictive value of cervical cancer severity with 94.0% sensitivity, 56.5% specificity, 88.8% positive predictive value, and 72.2% negative predictive value (Zhang et al., 2013).
Entity name
Colorectal cancer
Note
MCM7 expression was an independent prognostic factor for colorectal cancer, and MCM7-positive tumors correlated with increased metastasis rates (Nishihara et al., 2008). High MCM7 expression was also associated with adverse clinical outcome in colorectal cancer patients who underwent surgery for the primary tumor (Pillaire et al., 2010). In agreement, MCM7-positive Dukes C colorectal cancer patients presented lower overall survival and event-free survival (Ishibashi et al., 2014). Using quantitative PCR, Shi and colleagues (Shi et al., 2018) reported that MCM7 is one of the main genes involved in colorectal cancer progression. Recently, a meta-analysis has indicated MCM7 as a potential biomarker for colorectal cancer (Long et al., 2016).
Using a cohort of 13 anal cancer patients treated with radiation or without additional chemotherapy, Bruland and colleagues (Kreuter et al., 2010) described that the MCM7 protein was associated with better relapse-free survival and cancer-specific survival. The authors also highlighted that MCM7 may be regulated by the transcription factor E2F and induced by HPV. In anal intraepithelial high-grade neoplasm, the MCM protein family, including MCM7, was a marker of high-grade lesions and HPV-DNA load (Kreuter et al., 2010).
Entity name
Cutaneous diseases
Note
Using malignant and premalignant cultured cells from cutaneous diseases, Hiraiwa and colleagues (Hiraiwa et al., 1998) reported that MCM7 expression presented good correlations with clinical, microscopic, and biological malignancy characteristics.
Entity name
Note
Using microarray analysis, low MCM7 was observed in desmoid tumors, which may be associated with the reduced mitotic activity observed in this kind of tumors (Ferenc et al., 2010).
Entity name
Endometrial cancer
Note
High MCM7 was a reliable marker for the diagnosis of endometrial carcinoma, which was also associated with high histological grade and poor survival outcomes (multivariate analysis) (Li et al., 2005). Similarly, MCM7 expression was upregulated in endometrial cancer compared to the normal adjacent tissues (Zhao et al., 2012).
Entity name
Head and neck cancer
Note
Microarray analysis identified MCM7, among the six genes overexpressed in hypopharyngeal tumors, which was also associated with disease aggressiveness (Cromer et al., 2004). Similarly, MCM7 was increased in salivary tumors compared to normal salivary tissues and the high MCM7 expression was associated with advanced stage, invasion of adjacent tissue, invasion of the nerve, and poor clinical outcomes (Wen et al., 2018).
Using a murine model of head and neck squamous cell carcinoma, MCM7 was found as a potential biomarker for distinguishing HPV-positive and HPV-negative tumors (Strati et al., 2006).
Entity name
Hepatocellular carcinoma
Note
MCM7 expression was higher in hepatocellular carcinoma compared with non-tumor liver samples (Iizuka et al., 2006; Karavias et al., 2016; Qu et al., 2017; Wang et al., 2019; Yen et al., 2016). MCM7-positive hepatocellular carcinoma was associated with hepatitis, intrahepatic metastasis, vascular invasion, cell differentiation, tumor size, and shorter overall survival (Qu et al., 2017; Wang et al., 2019; Zhou et al., 2012).
In a cohort of 1300 cases of HBV-positive hepatocellular carcinoma, 1344 HBV-persistent, and 1344 individuals with natural HBV clearance, the AG/GG genotypes of the MCM7 polymorphism, rs999885, presented a decreased risk of chronic HBV infection in natural HBV clearance subjects. On the other hand, AG/GG genotypes negatively impacted the risk for the development of hepatocellular carcinoma in HBV persistent carriers (Liu et al., 2012a).
In univariate analysis, the G/G genotype of polymorphism in MCM7, rs2070215, impacted the risk for the development of the disease in a cohort containing 1019 hepatocellular carcinoma patients and 1138 healthy individuals (Nan et al., 2016). In hepatoma cells, MCM7 was downregulated by histone deacetylase inhibitor SAHA (Yang et al., 2015).
MCM7 shRNA lentivirus-mediated silencing reduced malignant behavior, suppressing proliferation, cell cycle progression, survival, and invasiveness, in MHCC-97H cells (Liu et al., 2015). Similarly, MCM7 silencing significantly reduced cellular proliferation in vitro and hepatocellular carcinoma tumorigenicity in vivo (Qu et al., 2017).
Using bioinformatics tools, MCM7 gene expression was identified as a potential biomarker for diagnosis and prognosis in hepatocellular carcinoma (Liao et al., 2018b; Liu et al., 2019). MCM7 expression was found to be a complementary and more effective prognostic marker compared to alpha-fetal protein in hepatocellular carcinoma (Xiang et al., 2019; Yu et al., 2018). Therefore, MCM7 was also identified as a protein with clinical relevance in hepatocellular carcinoma by PCT-SWATH (pressure-cycling technology applied to sequential window acquisition of all theoretical mass spectra) (Zhu et al., 2019).
Arsenic trioxide reduced MCM7 expression, which recapitulates the effects of MCM7 silencing on tumor suppression murine models of hepatocellular carcinoma, suggesting that arsenic trioxide may benefit from the treatment of this disease (Wang et al., 2019).
Entity name
Gastric cancer
Note
Using array comparative genomic hybridization, the amplification of 7q22.1 was observed in samples from gastroesophageal adenocarcinomas, and despite the positive correlation between the expression of MCM7 mRNA and protein, no association was observed with the genomic data (van Dekken et al., 2009).
MCM7 expression was upregulated in tumors compared to non-tumor gastric tissues, and its nuclear expression was associated with advanced age and poor disease-specific survival. In normal gastric epithelial tissue, MCM7 was strictly expressed in the proliferative compartment (Kang et al., 2014). Of note, the combination of MCM7 and Ki-67 was a more sensitive proliferation marker to identify esophageal cancer, gastric carcinoma, and precancerous lesions (Huber et al., 2015; Yang et al., 2018).
MCM7 knockdown, by siRNA, suppressed cell proliferation, colony formation, and invasion, and induced late apoptosis in gastric cancer cell lines (Kang et al., 2014).
Entity name
Gliomas
Note
Bioinformatics tools identified that the genomic region containing the MCM7 gene was amplified in more than 80% of the present cases and quantitative PCR confirmed the upregulation of MCM7 in glioblastomas compared to normal tissues (Erkan et al., 2014). In grade II-IV gliomas, increasing MCM7 expression was an independent predictor of poor overall survival (Hua et al., 2014). Using immunohistochemistry, MCM7 was found to a better marker for identifying cells into cell cycle progression than MKI67 (Ki-67) and PCNA in glioblastoma (Facoetti et al., 2006).
In glioblastoma models, siRNA-mediated MCM7 knockdown reduced cell proliferation and inhibited tumor growth in the xenograft and orthotopic glioblastoma models in rats (Erkan et al., 2014).
Entity name
Leukemia
Note
The single nucleotide polymorphisms in MCM7, rs2070215, rs1534309, rs2307355, and rs17447273, were not associated with AML risk (103 AML patients and 241 healthy individuals), but the rs2070215 significantly associated with AML relapse and the C/C genotype of rs1534309 positively impacted on the survival of AML patients (Lee et al., 2017). The impact of single nucleotide polymorphisms on MCM7, rs2070215, rs1527423, and rs1534309, was also investigated in a cohort of 281 acute myeloid leukemia patients and 405 healthy individuals, and the allele C of rs2070215 presented an increased frequency in AML patients (Tripon et al., 2020). In addition, among the eight different haplotypes, two (G/A/T and C/A/T for rs1534309/rs1527423/rs2070215, respectively) were associated with AML risk, regardless of age and gender (Tripon et al., 2020).
Higher MCM7 expression was observed at relapse when compared to the time of diagnosis in MLL-rearranged pediatric acute myeloid leukemia (Verboon et al., 2016). In chronic myeloid leukemia cells, K562, MCM7 is highly expressed and its silencing by siRNA exerts anti-proliferative and pro-apoptotic effects (Tian et al., 2017)
Entity name
Lymphoma
Note
In Hodgkins lymphoma, MCM7 is highly expressed in asymptomatic patients. High MCM7 expression was associated with greater age, advanced stage of the disease, and negatively impacted overall survival in multivariate analysis (Marnerides et al., 2011). Using immunohistochemistry, MCM7 was found to be more frequently positive in primary cutaneous T-cell lymphoma samples compared to benign inflammatory dermatosis, and it was also correlated with Ki-67 and MCM3 expression (Jankowska-Konsur et al., 2015).
In lymphoproliferative skin disorders of T cells, MCM7 levels were observed in a greater expression of mycosis fungoides IIB--V and lymphomatoid papulosis compared to parapsoriasis in plaque and mycosis fungoides stage I-IIA (Gambichler et al., 2008).
Entity name
Lung cancer
Note
Fujioka and colleagues (Fujioka et al., 2009), evaluating MCM7 and Ki-67 expressions in lung adenocarcinoma, found that MCM7 may be an independent prognostic marker, especially in early-stage tumors. MCM7-positive cells were absent in non-neoplastic alveolar epithelia and it was significantly higher in the peripheral area of the tumor (Fujioka et al., 2009). High scores for MCM7 expression were correlated with male gender, high histological grade, worse histological subtype, and increased tumor size and worse prognosis. Latterly, the same research group has shown how MCM7 expression was decisive for the creation of a prognostic score, based on proteins expressed in different phases of the cell cycle. Thus, the scores containing proteins expressed in G1/S (MCM7+/Ki-67+/Geminin+) and S/G2/M (MCM7+/ AURKA +/p-Histone H3S10+) presented worse clinical outcomes than MCM7-negative patients (G0) (Haruki et al., 2012).
In agreement, another study reported that MCM7 expression was significantly higher in lung cancer tissues, and its high expression correlated with poor prognosis in non-small cell lung cancer (Toyokawa et al., 2011). The authors also showed that combination therapy of histone deacetylase inhibition by a novel HDAC inhibitor, YF454A, with erlotinib to overcome EGFR -TKI resistance in in vitro and in vivo non-small cell lung cancer growth, by blocking MCM7 expression (Toyokawa et al., 2011).
In squamous cell carcinoma and lung adenocarcinoma, MCM7 levels in bronchial brushings were correlated with patient gender, tumor type, and tumor location (Liu et al., 2012b), indicating that MCM7 may be used as a protein marker for the early detection of bronchial brushing lung cancer (Liu et al., 2014). Recently, the role of MCM7 as a diagnosis marker for lung cancer has been confirmed by employing the Granger causality test (Fan et al., 2019).
Zhong and colleagues (Zhong et al., 2014a; Zhong et al., 2014b) reported that positive MCM7 expression was associated with positive NEK2 and Ki-67 expression, which was an independent prognostic factor for survival in resected non-small cell lung cancer patients, and the combined expression of MCM7/Ki-67 with NEK2 improved prognostic prediction, in which patients who had positive NEK2 expressions and positive MCM7/Ki-67 presented a lower survival rate than patients with negative expressions for these markers (Zhong et al., 2014a; Zhong et al., 2014b).
In non-small cell lung cancer cells, MCM7 phosphorylation was regulated by RACK1 through the MCM7/RACK1/AKT complex, resulting in an increase of the oncogenic potential of these cells (Fei et al., 2017). MCM7 expression had also been correlated with LMNB2 levels, and the high expression of both proteins was correlated with high tumor TNM stage, moderate-poor differentiation, and shorter overall survival of non-small cell lung cancer patients (Ma et al., 2017). Lo Sardo and colleagues (Lo Sardo et al., 2017) added novel insights for MCM7-mediated oncogenic pathways in lung cancer, by the interaction of MCM7 and YAP1 / TAZ, which impacted cell proliferation by CDKN1A inhibition.
Entity name
Medulloblastoma
Note
MCM7 overexpression increased anchorage-independent cell growth, migration, and invasion in medulloblastoma cells (Lau et al., 2010).
Entity name
Meningioma
Note
MCM7 was highly expressed in meningioma compared to arachnoid tissues (Saydam et al., 2010), suggesting a potential role for this protein as a diagnostic marker. Similar findings were observed in recurrent meningiomas compared with non-recurrent meningiomas and the ROC curve indicated that MCM7 expression had a high sensitivity for disease recurrence (Winther and Torp, 2017). A higher percentage of MCM7-positive cells was also associated with reduced recurrence-free survival in multivariate analysis (Winther and Torp, 2017).
Entity name
Neuroblastoma
Note
In neuroblastoma, MCM7 was found to be a target of MYCN transcription factor, once it is highly expressed in tumors with MYCN amplification (Shohet et al., 2002). In contrast, another study indicated that MCM7 overexpression is not necessarily correlated with MYCN amplification or an aggressive clinical course in neuroblastoma (Tsai et al., 2004).
Functional assays using a neuroblastoma cell line with inducible MYCN expression indicated that the increased rate of cells entering the S-phase and enhancing DNA replication machinery may be associated with the expression of MCM7 (Koppen et al., 2007).
Entity name
Ovarian cancer
Note
In a cohort of 342 ovarian cancer patients, increased MCM7 expression was observed in high-grade serous tissues (Ota et al., 2011). Similar findings were reported by Kobierzycki and colleagues (Kobierzycki et al., 2013). In contrast, higher MCM7 expression was associated with better progression-free survival (Ota et al., 2011).
Entity name
Pancreatic cancer
Note
Using microarray and immunohistochemistry analysis, high MCM7 expression was found in samples from pancreatic ductal adenocarcinoma patients (Grutzmann et al., 2004; Liang et al., 2014). In agreement, the MCM family, including MCM7, has been upregulated in pancreatic tumor tissues (Liao et al., 2018a).
In a retrospective cohort of pancreatic neuroendocrine neoplasm patients (n=156), the high expression of MCM7 was significantly associated with larger tumor size, non-functioning tumor, high grade, and TNM stage, and it was an independent prognostic factor for tumor progression (Ban et al., 2019).
Entity name
Pituitary adenoma
Note
High nuclear MCM7 expression was associated with a shorter recurrence/progression-free survival in a cohort of 97 pituitary adenoma patients. Moreover, among patients with invasive tumors, high MCM7 identified those with the highest risk of recurrence/progression (Coli et al., 2016).
Entity name
Prostate cancer
Note
Comparing MCM7 and Ki-67 expression as proliferation markers in prostate cancer, MCM7 was a better discriminatory marker for proliferation between benign epithelium, prostatic intraepithelial neoplasia, and invasive adenocarcinoma (Levesque et al., 2007; Majid et al., 2010; Padmanabhan et al., 2004).
MCM7 amplification or overexpression was associated with relapse, local invasion, and worse degree of the tumor (Ren et al., 2006). In prostate cancer patients treated with prostatectomy, high MCM7 was associated with a high Gleason score and was an independent shorter progression-free survival factor (Laitinen et al., 2008). Similar findings were reported by Tolonem and colleagues (Tolonen et al., 2011).
Evaluating cell proliferation and apoptosis profile in prostate aging in adult male Wistar rats, MCM7 was identified as a promising marker for the early detection of pre-malignant diseases (Gonzaga et al., 2017).
In DU145 cells, constitutive MCM7 expression resulted in marked DNA synthesis, cell proliferation, and invasion in vitro assays, and larger tumors and reduced mice survival in vivo assay (Ren et al., 2006). In agreement, MCM7 inhibition decreased tumor volume, metastases, and improved survival in xenograft DU145 and PC3 tumors mice (Shi et al., 2010).
Entity name
Renal cancer
Note
The levels of expression of the members of the MCM family, including MCM7, were higher in renal cell carcinoma compared to the paired adjacent normal tissue. Primary renal cell carcinoma patients overexpressing two or more MCM-related genes and metastatic renal cell carcinoma patients overexpressing three or more MCM-related genes presented shorter disease-free survival (Zhong et al., 2017).
Entity name
Retinoblastoma
Note
Using data-mining tools and validation by real-time RT-PCR and tissue microarrays in retinoblastoma and normal human retina samples, MCM7 was identified as a potential therapeutic target in retinoblastoma (Yang et al., 2008).
Entity name
Squamous cell carcinomas
Note
Using a murine model with deregulated MCM7 expression on the basal layer of the epidermis, Honeycutt and colleagues (Honeycutt et al., 2006) concluded that MCM7 actively contributes to the formation of tumors, progression and malignant conversion of squamous cell carcinomas of the skin.
Increased MCM7 expression was associated with lymph node metastasis and high tumor grade in precancerous lesions and oral squamous cell carcinoma (Feng et al., 2008). In agreement, MCM7 expression was highly expressed in dysplasias and oral squamous cell carcinoma compared to normal epithelia, and its aberrant expression was associated with high histological grade, poorly differentiated tumors, and poor survival outcomes (Tamura et al., 2010).
In oesophageal squamous cell carcinoma, MCM7 was also associated with histological factors, tumor depth, lymph node metastasis, tumor stage, and G9a expression. Double-positive expression for EHMT2 (G9a) and MCM7 oesophageal squamous cell carcinoma patients (G9a+/MCM7+) presented shorter survival compared to those with low G9a or MCM7 expression (G9a-/MCM7-), (G9a+/MCM7-), (G9a-/MCM7+) (Zhong et al., 2015). Recently, Qiu and colleagues (Qiu et al., 2017) have reported that MCM7 is amplified in 12% of esophageal squamous cell carcinomas and > 4% of head and neck squamous cell carcinomas and stomach carcinomas patients from the TCGA data. MCM7 overexpression was confirmed in three GEO independent data sets for esophageal cancer. MCM7 silencing by siRNAs inhibited cell proliferation, colony formation, and migration in KYSE510 and EC9706 cells. MCM7 depletion also suppressed AKT/mTOR activation, and cell cycle-related regulatory proteins, CCND1, CCNE2, and CDK2 (Qiu et al., 2017).
MCM7 expression significantly correlated with Ki-67, BMI1, and CCNE1 expression, and MCM4 and MCM7 were sensitive proliferation markers in esophageal carcinoma and precancerous lesions (Choy et al., 2016). Using bioinformatics analysis of gene expression data, Wang and colleagues (Wang et al., 2015) highlighted that MCM7 belongs to critical genes for head and neck squamous cell carcinoma.
In laryngeal squamous cell carcinoma, MCM7 expression was associated with EGFR (HER1) expression, and its high expression increased risk for disease progression, benign an independent prognostic factor overall survival, and progression-free survival (Almadori et al., 2017). In addition, MCM7 expression presented a strong correlation with Ki-67 in laryngeal squamous cell cancer (Nowinska et al., 2016).
Entity name
Note
MCM7 was found to be a target of MYCN in synovial sarcoma (Somers et al., 2007).
Entity name
Thyroid cancer
Note
Using cDNA array, MCM7 upregulation was observed in malignant thyroid neoplasms compared to benign thyroid neoplasms, being more expressed in high graded and locally invasive tumors. MCM7 combined with MCM5 and RAD9A mRNA levels showed 98.2% sensitivity and 65.7% specificity as a predictor of malignancy (Kebebew et al., 2006). In anaplastic thyroid carcinoma cells, MCM7 was overexpressed compared to normal thyroid cells, which was related to TP53 activity (Guida et al., 2005).

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308421442019Minichromosome Maintenance Proteins MCM-3, MCM-5, MCM-7, and Ki-67 as Proliferative Markers in Adrenocortical Tumors.Aporowicz M et al
304472992019High minichromosome maintenance protein 7 proliferation indices: a powerful predictor of progression in pancreatic neuroendocrine neoplasms without distant metastasis at the time of surgery.Ban X et al
146789722003Comparative analysis of cervical cancer in women and in a human papillomavirus-transgenic mouse model: identification of minichromosome maintenance protein 7 as an informative biomarker for human cervical cancer.Brake T et al
274767762016MCM4 and MCM7, potential novel proliferation markers, significantly correlated with Ki-67, Bmi1, and cyclin E expression in esophageal adenocarcinoma, squamous cell carcinoma, and precancerous lesions.Choy B et al
266203902016Minichromosome maintenance protein 7 as prognostic marker of tumor aggressiveness in pituitary adenoma patients.Coli A et al
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167033982006Involvement of c-myc-regulated genes in hepatocellular carcinoma related to genotype-C hepatitis B virus.Iizuka N et al
250751012014Minichromosome maintenance protein 7 is a risk factor for recurrence in patients with Dukes C colorectal cancer.Ishibashi Y et al
303695612018Regulation of MCM2-7 function.Ishimi Y et al
265040252015Expression of MCM-3 and MCM-7 in Primary Cutaneous T-cell Lymphomas.Jankowska-Konsur A et al
246474622014MCM7 serves as a prognostic marker in diffuse-type gastric adenocarcinoma and siRNA-mediated knockdown suppresses its oncogenic function.Kang W et al
264083312016Overexpression of CDT1 Is a Predictor of Poor Survival in Patients with Hepatocellular Carcinoma.Karavias D et al
224162532012A case study of human papillomavirus-associated bladder carcinoma developing after urethral condyloma acuminatum.Kawaguchi S et al
165476202006Diagnostic and prognostic value of cell-cycle regulatory genes in malignant thyroid neoplasms.Kebebew E et al
269667282016Upregulated expression of BCL2, MCM7, and CCNE1 indicate cisplatin-resistance in the set of two human bladder cancer cell lines: T24 cisplatin sensitive and T24R2 cisplatin resistant bladder cancer cell lines.Kim SH et al
243240722013Comparison of minichromosome maintenance proteins (MCM-3, MCM-7) and metallothioneins (MT-I/II, MT-III) expression in relation to clinicopathological data in ovarian cancer.Kobierzycki C et al
178269802007Direct regulation of the minichromosome maintenance complex by MYCN in neuroblastoma.Koppen A et al
200064072010Expression of proliferative biomarkers in anal intraepithelial neoplasia of HIV-positive men.Kreuter A et al
97058681998Human papillomavirus oncoprotein E6 binds to the C-terminal region of human minichromosome maintenance 7 protein.Kukimoto I et al
179437222008EZH2, Ki-67 and MCM7 are prognostic markers in prostatectomy treated patients.Laitinen S et al
206612202010Minichromosome maintenance proteins 2, 3 and 7 in medulloblastoma: overexpression and involvement in regulation of cell migration and invasion.Lau KM et al
278372512017MCM7 polymorphisms associated with the AML relapse and overall survival.Lee JS et al
172706582007Evaluation of AIbZIP and Cdc47 as markers for human prostatic diseases.Levesque MH et al
157204162005Replicative MCM7 protein as a proliferation marker in endometrial carcinoma: a tissue microarray and clinicopathological analysis.Li SS et al
255027772014Identification of genomic alterations in pancreatic cancer using array-based comparative genomic hybridization.Liang JW et al
281507532017Simvastatin suppresses the DNA replication licensing factor MCM7 and inhibits the growth of tamoxifen-resistant breast cancer cells.Liang Z et al
302332422018Prognostic value of minichromosome maintenance mRNA expression in early-stage pancreatic ductal adenocarcinoma patients after pancreaticoduodenectomy.Liao X et al
300268322018Distinct Diagnostic and Prognostic Values of Minichromosome Maintenance Gene Expression in Patients with Hepatocellular Carcinoma.Liao X et al
316959692019Identification of key genes and long non-coding RNA associated ceRNA networks in hepatocellular carcinoma.Liu J et al
263094962015Biological effects of lentivirus-mediated silencing of minichromosome maintenance protein 7 with shRNA on the liver cancer MHCC-97H cells.Liu J et al
223933902012A genetic variant in the promoter region of miR-106b-25 cluster and risk of HBV infection and hepatocellular carcinoma.Liu Y et al
250450142014A panel of protein markers for the early detection of lung cancer with bronchial brushing specimens.Liu YZ et al
277978252017MCM7 and its hosted miR-25, 93 and 106b cluster elicit YAP/TAZ oncogenic activity in lung cancer.Lo Sardo F et al
276887072016Novel Biomarker Candidates for Colorectal Cancer Metastasis: A Meta-analysis of In Vitro Studies.Long NP et al
212676862011Expression of 11β-hydroxysteroid dehydrogenase type 1 in breast cancer and adjacent non-malignant tissue. An immunocytochemical study.Lu L et al
292852162017Lamin B2 binding to minichromosome maintenance complex component 7 promotes non-small cell lung carcinogenesis.Ma Y et al
203322392010Regulation of minichromosome maintenance gene family by microRNA-1296 and genistein in prostate cancer.Majid S et al
219657822011Immunohistochemical expression and prognostic significance of CCND3, MCM2 and MCM7 in Hodgkin lymhoma.Marnerides A et al
273507342016Relationships between cell cycle pathway gene polymorphisms and risk of hepatocellular carcinoma.Nan YL et al
186361442008Minichromosome maintenance protein 7 in colorectal cancer: implication of prognostic significance.Nishihara K et al
266484052016Correlation between levels of expression of minichromosome maintenance proteins, Ki-67 proliferation antigen and metallothionein I/II in laryngeal squamous cell cancer.Nowinska K et al
210764602011Minichromosome maintenance protein 7 as a potential prognostic factor for progression-free survival in high-grade serous carcinomas of the ovary.Ota T et al
154521602004DNA replication regulation protein Mcm7 as a marker of proliferation in prostate cancer.Padmanabhan V et al
199019682010A 'DNA replication' signature of progression and negative outcome in colorectal cancer.Pillaire MJ et al
284984602017MCM7 amplification and overexpression promote cell proliferation, colony formation and migration in esophageal squamous cell carcinoma by activating the AKT1/mTOR signaling pathway.Qiu YT et al
281820152017MCM7 promotes cancer progression through cyclin D1-dependent signaling and serves as a prognostic marker for patients with hepatocellular carcinoma.Qu K et al
162474662006MCM7 amplification and overexpression are associated with prostate cancer progression.Ren B et al
198777192010Comparative protein profiling reveals minichromosome maintenance (MCM) proteins as novel potential tumor markers for meningiomas.Saydam O et al
291799872018Identification of genes involved in the four stages of colorectal cancer: Gene expression profiling.Shi G et al
205393232010Inhibition of prostate cancer growth and metastasis using small interference RNA specific for minichromosome complex maintenance component 7.Shi YK et al
215237182011Etiologic role of human papillomavirus infection in bladder carcinoma.Shigehara K et al
118613922002Minichromosome maintenance protein MCM7 is a direct target of the MYCN transcription factor in neuroblastoma.Shohet JM et al
174643172007Expression of MYCN in pediatric synovial sarcoma.Somers GR et al
169309942006Expression of aromatase and 17beta-hydroxysteroid dehydrogenase types 1, 7 and 12 in breast cancer. An immunocytochemical study.Song D et al
169598852006Identification of biomarkers that distinguish human papillomavirus (HPV)-positive versus HPV-negative head and neck cancers in a mouse model.Strati K et al
97147541998Cloning and characterization of human MCM7 promoter.Suzuki S et al
201366982010Minichromosome maintenance-7 and geminin are reliable prognostic markers in patients with oral squamous cell carcinoma: immunohistochemical study.Tamura T et al
280586292017RNAi-mediated knockdown of MCM7 gene on CML cells and its therapeutic potential for leukemia.Tian L et al
215922982011Histopathological variables and biomarkers enhancer of zeste homologue 2, Ki-67 and minichromosome maintenance protein 7 as prognosticators in primarily endocrine-treated prostate cancer.Tolonen TT et al
216196712011Minichromosome Maintenance Protein 7 is a potential therapeutic target in human cancer and a novel prognostic marker of non-small cell lung cancer.Toyokawa G et al
319362152020Modelling the Effects of MCM7 Variants, Somatic Mutations, and Clinical Features on Acute Myeloid Leukemia Susceptibility and Prognosis.Tripon F et al
156688982004Correlation of MYCN amplification with MCM7 protein expression in neuroblastomas: a chromogenic in situ hybridization study in paraffin sections.Tsai HY et al
273512222016MicroRNA-106b~25 cluster is upregulated in relapsed MLL-rearranged pediatric acute myeloid leukemia.Verboon LJ et al
267823822015Critical genes in head and neck squamous cell carcinoma revealed by bioinformatic analysis of gene expression data.Wang B et al
311864052019Arsenic trioxide inhibits liver cancer stem cells and metastasis by targeting SRF/MCM7 complex.Wang HY et al
319496172018Expression and prognostic significance of MCM-3 and MCM-7 in salivary adenoid cystic carcinoma.Wen QL et al
278681572017MCM7 expression is a promising predictor of recurrence in patients surgically resected for meningiomas.Winther TL et al
230984542012Transcription regulation network analysis of MCF7 breast cancer cells exposed to estradiol.Wu JZ et al
310112562019Seven-senescence-associated gene signature predicts overall survival for Asian patients with hepatocellular carcinoma.Xiang XH et al
253933672015Histone deacetylase inhibitor SAHA epigenetically regulates miR-17-92 cluster and MCM7 to upregulate MICA expression in hepatoma.Yang H et al
183503062008Identification of candidate cancer genes involved in human retinoblastoma by data mining.Yang J et al
285404862018The Expression of MCM7 is a Useful Biomarker in the Early Diagnostic of Gastric Cancer.Yang JY et al
272985612016miR-106b promotes cancer progression in hepatitis B virus-associated hepatocellular carcinoma.Yen CS et al
149909952004Regulation of Geminin and Cdt1 expression by E2F transcription factors.Yoshida K et al
294422752018Five Novel Oncogenic Signatures Could Be Utilized as AFP-Related Diagnostic Biomarkers for Hepatocellular Carcinoma Based on Next-Generation Sequencing.Yu Z et al
267222522015Cantharidin modulates the E2F1/MCM7-miR-106b-93/p21-PTEN signaling axis in MCF-7 breast cancer cells.Zhang H et al
233189112013The protein levels of MCM7 and p63 in evaluating lesion severity of cervical disease.Zhang J et al
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291808992017Expression of minichromosome maintenance genes in renal cell carcinoma.Zhong H et al
248050872015Overexpression of G9a and MCM7 in oesophageal squamous cell carcinoma is associated with poor prognosis.Zhong X et al
252023512014Aberrant expression of NEK2 and its clinical significance in non-small cell lung cancer.Zhong X et al
227840962012MCM7 expression predicts post-operative prognosis for hepatocellular carcinoma.Zhou YM et al
303652252019Identification of Protein Abundance Changes in Hepatocellular Carcinoma Tissues Using PCT-SWATH.Zhu Y et al
191676102009Array comparative genomic hybridization, expression array, and protein analysis of critical regions on chromosome arms 1q, 7q, and 8p in adenocarcinomas of the gastroesophageal junction.van Dekken H et al

Other Information

Locus ID:

NCBI: 4176
MIM: 600592
HGNC: 6950
Ensembl: ENSG00000166508

Variants:

dbSNP: 4176
ClinVar: 4176
TCGA: ENSG00000166508
COSMIC: MCM7

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000166508ENST00000303887P33993
ENSG00000166508ENST00000303887A0A0S2Z4A5
ENSG00000166508ENST00000343023P33993
ENSG00000166508ENST00000354230P33993
ENSG00000166508ENST00000425308C9J8M6
ENSG00000166508ENST00000491245H0YH42
ENSG00000166508ENST00000621318P33993

Expression (GTEx)

0
50
100
150
200

Pathways

PathwaySourceExternal ID
DNA replicationKEGGko03030
Cell cycleKEGGko04110
DNA replicationKEGGhsa03030
Cell cycleKEGGhsa04110
MCM complexKEGGhsa_M00285
MCM complexKEGGM00285
Cell CycleREACTOMER-HSA-1640170
Cell Cycle CheckpointsREACTOMER-HSA-69620
G2/M CheckpointsREACTOMER-HSA-69481
Activation of ATR in response to replication stressREACTOMER-HSA-176187
Cell Cycle, MitoticREACTOMER-HSA-69278
Mitotic G1-G1/S phasesREACTOMER-HSA-453279
G1/S TransitionREACTOMER-HSA-69206
Activation of the pre-replicative complexREACTOMER-HSA-68962
S PhaseREACTOMER-HSA-69242
Synthesis of DNAREACTOMER-HSA-69239
Switching of origins to a post-replicative stateREACTOMER-HSA-69052
Orc1 removal from chromatinREACTOMER-HSA-68949
DNA strand elongationREACTOMER-HSA-69190
Unwinding of DNAREACTOMER-HSA-176974
Regulation of DNA replicationREACTOMER-HSA-69304
Removal of licensing factors from originsREACTOMER-HSA-69300
M/G1 TransitionREACTOMER-HSA-68874
DNA Replication Pre-InitiationREACTOMER-HSA-69002
Assembly of the pre-replicative complexREACTOMER-HSA-68867
DNA ReplicationREACTOMER-HSA-69306

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
203889162010Identification of the miR-106b~25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation.185
152109352004Minichromosome maintenance proteins are direct targets of the ATM and ATR checkpoint kinases.137
198052162009Assembly of the Cdc45-Mcm2-7-GINS complex in human cells requires the Ctf4/And-1, RecQL4, and Mcm10 proteins.88
162474662006MCM7 amplification and overexpression are associated with prostate cancer progression.68
196967452009MCM10 mediates RECQ4 association with MCM2-7 helicase complex during DNA replication.65
146789722003Comparative analysis of cervical cancer in women and in a human papillomavirus-transgenic mouse model: identification of minichromosome maintenance protein 7 as an informative biomarker for human cervical cancer.52
194016822010High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility.52
155383882004Interaction between human MCM7 and Rad17 proteins is required for replication checkpoint signaling.43
216196712011Minichromosome Maintenance Protein 7 is a potential therapeutic target in human cancer and a novel prognostic marker of non-small cell lung cancer.41
206612202010Minichromosome maintenance proteins 2, 3 and 7 in medulloblastoma: overexpression and involvement in regulation of cell migration and invasion.32

Citation

Keli Lima ; Eduardo Magalhães Rego ; Joao Agostinho Machado-Neto

MCM7 (minichromosome maintenance complex component 7)

Atlas Genet Cytogenet Oncol Haematol. 2020-09-01

Online version: http://atlasgeneticsoncology.org/gene/41323/mcm7