7q22.1

CDC47,MCM2,P1.1-MCM3,P1CDC47,P85MCM,PNAS146,PPP1R104

Adrenocortical carcinomas

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.

Bladder cancer

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).

Breast cancer

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).

Cervical cancer

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).

Colorectal cancer

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).

Cutaneous diseases

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.

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).

Endometrial cancer

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).

Head and neck cancer

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).

Hepatocellular carcinoma

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).

Gastric cancer

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).

Gliomas

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).

Leukemia

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)

Lymphoma

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).

Lung cancer

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.

Medulloblastoma

MCM7 overexpression increased anchorage-independent cell growth, migration, and invasion in medulloblastoma cells (Lau et al., 2010).

Meningioma

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).

Neuroblastoma

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).

Ovarian cancer

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).

Pancreatic cancer

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).

Pituitary adenoma

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).

Prostate cancer

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).

Renal cancer

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).

Retinoblastoma

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).

Squamous cell carcinomas

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).

MCM7 was found to be a target of MYCN in synovial sarcoma (Somers et al., 2007).

Thyroid cancer

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).