Gene Summary

Gene:MCM2; minichromosome maintenance complex component 2
Aliases: BM28, CCNL1, CDCL1, cdc19, D3S3194, MITOTIN
Summary:The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are involved in the initiation of eukaryotic genome replication. The hexameric protein complex formed by MCM proteins is a key component of the pre-replication complex (pre_RC) and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. This protein forms a complex with MCM4, 6, and 7, and has been shown to regulate the helicase activity of the complex. This protein is phosphorylated, and thus regulated by, protein kinases CDC2 and CDC7. Multiple alternatively spliced transcript variants have been found, but the full-length nature of some variants has not been defined. [provided by RefSeq, Oct 2012]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:DNA replication licensing factor MCM2
Source:NCBIAccessed: 25 June, 2015


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 25 June 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 25 June, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MCM2 (cancer-related)

Hoskins JW, Jia J, Flandez M, et al.
Transcriptome analysis of pancreatic cancer reveals a tumor suppressor function for HNF1A.
Carcinogenesis. 2014; 35(12):2670-8 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is driven by the accumulation of somatic mutations, epigenetic modifications and changes in the micro-environment. New approaches to investigating disruptions of gene expression networks promise to uncover key regulators and pathways in carcinogenesis. We performed messenger RNA-sequencing in pancreatic normal (n = 10) and tumor (n = 8) derived tissue samples, as well as in pancreatic cancer cell lines (n = 9), to determine differential gene expression (DE) patterns. Sub-network enrichment analyses identified HNF1A as the regulator of the most significantly and consistently dysregulated expression sub-network in pancreatic tumor tissues and cells (median P = 7.56×10(-7), median rank = 1, range = 1-25). To explore the effects of HNF1A expression in pancreatic tumor-derived cells, we generated stable HNF1A-inducible clones in two pancreatic cancer cell lines (PANC-1 and MIA PaCa-2) and observed growth inhibition (5.3-fold, P = 4.5×10(-5) for MIA PaCa-2 clones; 7.2-fold, P = 2.2×10(-5) for PANC-1 clones), and a G0/G1 cell cycle arrest and apoptosis upon induction. These effects correlated with HNF1A-induced down-regulation of 51 of 84 cell cycle genes (e.g. E2F1, CDK2, CDK4, MCM2/3/4/5, SKP2 and CCND1), decreased expression of anti-apoptotic genes (e.g. BIRC2/5/6 and AKT) and increased expression of pro-apoptotic genes (e.g. CASP4/9/10 and APAF1). In light of the established role of HNF1A in the regulation of pancreatic development and homeostasis, our data suggest that it also functions as an important tumor suppressor in the pancreas.

Zhang W, Gong W, Ai H, et al.
Gene expression analysis of lung adenocarcinoma and matched adjacent non-tumor lung tissue.
Tumori. 2014 May-Jun; 100(3):338-45 [PubMed] Related Publications
AIMS AND BACKGROUND: The aim of this study was to find disease-associated genes and gene functions in lung adenocarcinoma and matched adjacent non-tumor lung tissues with DNA microarray.
METHODS: We downloaded the gene expression profile GSE32863 from the Gene Expression Omnibus database including 58 lung adenocarcinoma and 58 adjacent non-tumor lung tissue samples. Data were preprocessed and the differentially expressed genes (DEGs) were identified using packages in the R computing language. The selected DEGs were further analyzed with bioinformatics methods. After the coexpression network of DEGs was constructed by STRING (Search Tool for the Retrieval of Interacting Genes/Proteins), we analyzed gene functions with DAVID (The Database for Annotation, Visualization and Integrated Discovery) and WebGestalt (WEB-based Gene Set Analysis Toolkit).
RESULTS: A total of 1429 genes were filtered as DEGs, including 873 downregulated genes and 556 upregulated genes, and the DEGs including CDC45, CCNB2, CDC20, MCM2, PTTG1, MCM4 and FEN1 were most significantly related to cell cycle and DNA replication.
CONCLUSION: The discovery of featured genes which were significantly related to cell cycle and DNA replication has potential for use in the clinic for the diagnosis of lung adenocarcinoma in the future. However, further experiments will be needed to confirm our result.

Hua C, Zhao G, Li Y, Bie L
Minichromosome Maintenance (MCM) Family as potential diagnostic and prognostic tumor markers for human gliomas.
BMC Cancer. 2014; 14:526 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
BACKGROUND: Gliomas are the most common type of all central nervous system tumors. Almost all patients diagnosed with these tumors have a poor prognostic outcome. We aimed to identify novel glioma prognosis-associated candidate genes.
METHODS: We applied WebArrayDB software to span platform integrate and analyze the microarray datasets. We focused on a subset of the significantly up-regulated genes, the minichromosome maintenance (MCM) family. We used frozen glioma samples to predict the relationship between the expression of MCMs and patients outcome by qPCR and western blot.
RESULTS: We found that MCMs expression was significantly up-regulated in glioma samples. MCM2-7 and MCM10 expressions were associated with WHO tumor grade. High MCM2 mRNA expression appeared to be strongly associated with poor overall survival in patients with high grade glioma. Furthermore, we report that MCM7 is strongly correlated with patient outcome in patients with WHO grade II-IV tumor. MCM3 expression was found to be up-regulated in glioma and correlated with overall survival in patients with WHO grade III tumor. MCM2, MCM3 and MCM7 expression levels were of greater prognostic relevance than histological diagnosis according to the current WHO classification system.
CONCLUSIONS: High expression of MCM 2, MCM3 and MCM7 mRNA correlated with poor outcome and may be clinically useful molecular prognostic markers in glioma.

Ichinose J, Watanabe K, Sano A, et al.
Alternative polyadenylation is associated with lower expression of PABPN1 and poor prognosis in non-small cell lung cancer.
Cancer Sci. 2014; 105(9):1135-41 [PubMed] Related Publications
Alternative polyadenylation (APA), which induces shortening of the 3'UTR, is emerging as an important phenomenon in gene regulation. APA is involved in development, cancer and cell proliferation. APA may lead to disruption of microRNA-mediated gene silencing in cancer cells via detachment of microRNA binding sites. We studied the correlation between the APA profile and the tumor aggressiveness in cases of lung cancer. We selected the top 10 genes showing significant 3'UTR shortening in lung cancer, using the package of the Bioconductor for probe-level analyses of expression microarrays. We established and evaluated the APA score by quantitative RT-PCR in 147 clinical specimens of non-small cell lung cancer and compared the results with the clinical outcomes and expression levels of APA-related genes, including PABPN1, CPEB1, E2F1 and proliferation markers (MKI67, TOP2A and MCM2). High APA scores were correlated with an advanced tumor stage and a poor prognosis (P < 0.001). Multivariate analysis identified the APA score as an independent prognostic factor (hazard ratio, 3.0; P = 0.03). Both lower expression of PABPN1 and higher expression of the proliferation markers were correlated with high APA scores and a poor prognosis, with suppression of PABPN1 exerting its influence independent of gain of the proliferation markers. Moreover, the APA score was correlated with the maximum standardized uptake value of the tumors on positron emission tomography (r = 0.53; P < 0.001). Our results indicate that the loss of PABPN1, a suppressor of APA, might promote tumor aggressiveness by releasing the cancer cells from microRNA-mediated gene regulation.

Jin Y, Xiong A, Zhang Z, et al.
MicroRNA-31 suppresses medulloblastoma cell growth by inhibiting DNA replication through minichromosome maintenance 2.
Oncotarget. 2014; 5(13):4821-33 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Medulloblastoma is an aggressive childhood brain tumor with poor prognosis. Recent studies indicate that dys-regulation of microRNA expression plays important roles in tumorigenesis. By comparing microRNA levels between mouse medulloblastoma and normal cerebellar tissues, we identified a set of down-regulated microRNAs including miR-31. Here, we show that the genomic region surrounding human miR-31 at 9p21.3 is frequently deleted in many solid tumor cell lines, and reintroducing miR-31 into DAOY cells, a line of human medulloblastoma cells devoid of miR-31, strongly suppresses cell growth, causes cell cycle arrest at the G1/S boundary, and inhibits colony formation in vitro and xenograft tumorigenesis in nude mice. Global gene expression profiling of mouse medulloblastomas and bioinformatics analyses of microRNA targets suggest that minichromosome maintenance complex component 2 (MCM2) is a likely target gene of miR-31 in suppressing cell growth. We demonstrate that miR-31 inhibits MCM2 expression via its 3'-untranslated region, that knockdown of MCM2 in DAOY cells leads to a degree of growth inhibition comparable to that by miR-31 restoration, and that overexpression of miR-31 reduces the chromatin loading of MCM2 at the point of G1/S transition. Taken together, these data indicate that miR-31 suppresses medulloblastoma tumorigenesis by negatively regulating DNA replication via MCM2.

Liu D, Zhang XX, Xi BX, et al.
Sine oculis homeobox homolog 1 promotes DNA replication and cell proliferation in cervical cancer.
Int J Oncol. 2014; 45(3):1232-40 [PubMed] Related Publications
Malignant proliferation is the fundamental trait of tumor cells. The initiation of DNA replication represents a key process for cell proliferation, and has a marked impact on tumorigenesis and progression. Here we report that Sine oculis homeobox homolog 1 (SIX1) functions as a master regulator in DNA replication of cervical cancer cells. The expression of SIX1 was induced by the E7 oncoprotein of human papillomaviruses in cervical intraepithelial neoplasia and cervical cancer. The increase of SIX1 expression resulted in the upregulation of multiple genes related to the initiation of DNA replication, including the genes coding for the proteins in minichromosome maintenance complex (MCM2, MCM3, MCM6), DNA polymerase α-primase complex (POLA1, PRIM1, PRIM2), clamp loader (RFC3, RFC4, RFC5), DNA polymerase δ complex (POLD3) and DNA polymerase ε complex (POLE2). In line with this, the increase of SIX1 expression enhanced DNA synthesis, accelerated G1 to S phase progression, and promoted the proliferation of cervical cancer cells and the growth of cervical cancer. Consistently, knockdown of SIX1 could hamper DNA synthesis, slow down G1 to S phase progression, and suppress tumor cell proliferation and tumor growth. Importantly, SIX1 could more efficiently promote anchorage-independent cell growth. These results suggest that the increase of SIX1 expression could promote tumorigenesis, progression and invasive growth of cervical cancer by promoting DNA replication, and that targeting SIX1 may have significant therapeutic value in cervical cancer treatment.

Zali H, Rezaei Tavirani M
Meningioma protein-protein interaction network.
Arch Iran Med. 2014; 17(4):262-72 [PubMed] Related Publications
BACKGROUND: Meningioma is one of the most common central nervous system tumors that derived from meningothelial (arachnoid cap) cells. This paper identified the network-based Protein-Protein Interactions (PPI) for meningioma relative to healthy control.
METHODS: Gene expression data including 384 gene or protein names extracted from a number of beforehand investigations.
RESULTS: Out of these 384 proteins, 176 were found to be exclusively expressed in meningiomas and 208 proteins were down-regulated. The networks of related differentially expressed genes were explored using cytoscape and the PPI analysis methods such as MCODE and ClueGO. Results analysis introduced a number of hub proteins and 27 clusters (protein complex) with distinctive seed genes. Identified ClueGO Pathways based on subnetworks mined by MCODE composed of positive regulation in RBC homeostasis, dysregulation of transport from ER to Golgi, disruption regulation of cell cycle and antigen processing and presentation of exogenous peptide antigen and neutralization of exogenous dsRNA. Combination of over expression of TCEA1, UBE2E1, XRCC5, IFIT1, IFIT-3, MCM2, and MCM7 and under expression of CDC25A, SEC31A, and CDK6 can serve as diagnostic biomarker panel for meningiomas.
CONCLUSION: These introduced network-based biomarkers for the meningioma patterns may be helpful in diagnosis, prognosis and treatment processes however biomarker validation is necessary.

Miles KA, Ganeshan B, Rodriguez-Justo M, et al.
Multifunctional imaging signature for V-KI-RAS2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in colorectal cancer.
J Nucl Med. 2014; 55(3):386-91 [PubMed] Related Publications
UNLABELLED: This study explores the potential for multifunctional imaging to provide a signature for V-KI-RAS2 Kirsten rat sarcoma viral oncogene homolog (KRAS) gene mutations in colorectal cancer.
METHODS: This prospective study approved by the institutional review board comprised 33 patients undergoing PET/CT before surgery for proven primary colorectal cancer. Tumor tissue was examined histologically for presence of the KRAS mutations and for expression of hypoxia-inducible factor-1 (HIF-1) and minichromosome maintenance protein 2 (mcm2). The following imaging parameters were derived for each tumor: (18)F-FDG uptake ((18)F-FDG maximum standardized uptake value [SUVmax]), CT texture (expressed as mean of positive pixels [MPP]), and blood flow measured by dynamic contrast-enhanced CT. A recursive decision tree was developed in which the imaging investigations were applied sequentially to identify tumors with KRAS mutations. Monte Carlo analysis provided mean values and 95% confidence intervals for sensitivity, specificity, and accuracy.
RESULTS: The final decision tree comprised 4 decision nodes and 5 terminal nodes, 2 of which identified KRAS mutants. The true-positive rate, false-positive rate, and accuracy (95% confidence intervals) of the decision tree were 82.4% (63.9%-93.9%), 0% (0%-10.4%), and 90.1% (79.2%-96.0%), respectively. KRAS mutants with high (18)F-FDG SUVmax and low MPP showed greater frequency of HIF-1 expression (P = 0.032). KRAS mutants with low (18)F-FDG SUV(max), high MPP, and high blood flow expressed mcm2 (P = 0.036).
CONCLUSION: Multifunctional imaging with PET/CT and recursive decision-tree analysis to combine measurements of tumor (18)F-FDG uptake, CT texture, and perfusion has the potential to identify imaging signatures for colorectal cancers with KRAS mutations exhibiting hypoxic or proliferative phenotypes.

Lian M, Fang J, Han D, et al.
Microarray gene expression analysis of tumorigenesis and regional lymph node metastasis in laryngeal squamous cell carcinoma.
PLoS One. 2013; 8(12):e84854 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) is the most common type in head and neck squamous cell carcinoma (HNSCC), and the development and progression of LSCC are multistep processes accompanied by changes of molecular biology.
OBJECTIVE: The purpose of this study was to investigate the molecular basis of tumorigenesis and regional lymph node metastasis in LSCC, and provide a set of genes that may be useful for the development of novel diagnostic markers and/or more effective therapeutic strategies.
METHODS: A total number of 10 patients who underwent surgery for primary laryngeal squamous cell carcinoma were recruited for microarray analysis. LSCC tissues compared with corresponding adjacent non-neoplastic tissues were analysed by Illumina mRNA microarrays, and LSCC tissues with regional lymph node metastasis and LSCC tissues without regional lymph node metastasis were analyzed in the same manner. The most frequently differently expressed genes screened by microarrays were also validated by qRT-PCR in another 42 patients diagnosed for LSCC.
RESULTS: Analysed by Illumina mRNA microarrays, there were 361 genes significantly related to tumorigenesis while 246 genes significantly related to regional lymph node metastasis in LSCC. We found that the six genes (CDK1, CDK2, CDK4, MCM2, MCM3, MCM4) were most frequently differently expressed functional genes related to tumorigenesis while eIF3a and RPN2 were most frequently differently expressed functional genes related to regional lymph node metastasis in LSCC. The expressions of these genes were also validated by qRT-PCR.
CONCLUSIONS: The research revealed a gene expression signature of tumorigenesis and regional lymph node metastasis in laryngeal squamous cell carcinoma. Of the total, the deregulation of several genes (CDK1, CDK2, CDK4, MCM2, MCM3, MCM4, EIF3a and RPN2) were potentially associated with disease development and progression. The result will contribute to the understanding of the molecular basis of LSCC and help to improve diagnosis and treatment.

Tornesello ML, Buonaguro L, Giorgi-Rossi P, Buonaguro FM
Viral and cellular biomarkers in the diagnosis of cervical intraepithelial neoplasia and cancer.
Biomed Res Int. 2013; 2013:519619 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Cervical cancer arises from cells localized in the ectoendocervical squamocolumnar junction of the cervix persistently infected with one of about 13 human papillomavirus (HPV) genotypes. The majority of HPV infections induces low grade squamous epithelial lesions that in more than 90% of cases spontaneously regress and in about 10% eventually progress to high grade lesions and even less frequently evolve to invasive cancer. Tumor progression is characterized by (1) increased expression of E6 and E7 genes of high risk HPVs, known to bind to and inactivate p53 and pRb oncosuppressors, respectively; (2) integration of viral DNA into host genome, with disruption of E2 viral genes and host chromosomal loci; and (3) molecular alterations of key regulators of cell cycle. Molecular markers with high sensitivity and specificity in differentiating viral infections associated with cellular abnormalities with high risk of progression are strongly needed for cervical cancer screening and triage. This review will focus on the analysis of clinical validated or candidate biomarkers, such as HPV DNA, HPV E6/E7 mRNA, HPV proteins, p16(INK4a) and Ki67, TOP2A and MCM2 cellular factors, and DNA methylation profiles, which will likely improve the identification of premalignant lesions that have a high risk to evolve into invasive cervical cancer.

Das M, Prasad SB, Yadav SS, et al.
Over expression of minichromosome maintenance genes is clinically correlated to cervical carcinogenesis.
PLoS One. 2013; 8(7):e69607 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Minichromosome Maintenance (MCM) proteins play important roles in cell cycle progression by mediating DNA replication initiation and elongation. Among 10 MCM homologues MCM 2-7 form a hexamer and assemble to the pre-replication complex acting as replication licensing factors. Binding and function of MCM2-7 to pre-replication complex is regulated by MCM10 mediated binding of RECQL4 with MCM2-7. The purpose of this study is to explore the role of MCMs in cervical cancer and their correlation with the clinical parameters of cervical cancer. We have investigated sixty primary cervical cancer tissue samples, eight cervical cancer cell lines and thirty hysterectomised normal cervical tissue. The expression profiling of MCMs was done using semi-quantitative RT-PCR, immunoblotting and immunohistochemistry. MCM2, 4, 5, 6, 7, 10 and RECQL4 are significantly over-expressed in cervical cancer. Among these, MCM4, 6 and 10 show increased frequency of over expression along with advancement of tumor stages. MCM4, 5 and 6 also show differential expression in different types of lesion, while MCM2 and MCM10 are over expressed in cervical cancer irrespective of clinico-pathological parameters. Our data indicates the role of MCM4, MCM5, MCM6, MCM10 and RECQL4 in the progression of cervical cancer.

Coulombe P, Grégoire D, Tsanov N, Méchali M
A spontaneous Cdt1 mutation in 129 mouse strains reveals a regulatory domain restraining replication licensing.
Nat Commun. 2013; 4:2065 [PubMed] Related Publications
Cdt1 is required for loading the replicative DNA helicase MCM2/7, a process known as DNA replication licensing. Here we show that 129 mouse strains express a Cdt1 mutated allele with enhanced licensing activity. The mutation, named Δ(6)PEST, involves a six-amino acid deletion within a previously uncharacterized PEST-like domain. Cdt1 Δ(6)PEST and more extensive deletions exhibit increased re-replication and transformation activities that are independent of the Geminin and E3 ligase pathways. This PEST domain negatively regulates cell cycle-dependent chromatin recruitment of Cdt1 in G2/M phases of the cell cycle. Mass spectrometry analysis indicates that Cdt1 is phosphorylated at sites within the deleted PEST domain during mitosis. This study reveals a conserved new regulatory Cdt1 domain crucial for proper DNA licensing activity and suggests a mechanism by which the presence of Cdt1 in G2/M phases does not lead to premature origin licensing. These results also question the usage of 129 mouse strains for knockout analyses.

Liu Y, He G, Wang Y, et al.
MCM-2 is a therapeutic target of Trichostatin A in colon cancer cells.
Toxicol Lett. 2013; 221(1):23-30 [PubMed] Related Publications
Histone deacetylase (HDAC) inhibitors have recently emerged as a new class of anti-cancer agents. Trichostatin A (TSA), a classical HDAC inhibitor, has been demonstrated to induce cell cycle arrest, promote cell apoptosis, and inhibit metastasis. However, the molecular mechanism underlying TSA function has not been fully elucidated. In the current study, we found that TSA treatment induced altered expression of cell cycle-associated genes in HCT116 cells by RT-PCR array. Among the 84 genes related to cell cycle control, 34 genes were significantly altered by TSA treatment, with 7 genes upregulated and 27 genes downregulated. Interestingly, gene expression of minichromosome maintenance protein-2 (MCM-2) was significantly downregulated by TSA treatment. This was confirmed by quantitative RT-PCR and Western blotting. Moreover, silencing of MCM-2 by siRNA led to cell cycle arrest and apoptosis in HCT116 cells. In addition, TSA caused an increase of phosphorylated JNK, which was involved in downregulation of MCM-2. Together, our results suggest that MCM-2 is a noval therapeutic target of TSA in colon cancer cells.

Che Y, Best OG, Zhong L, et al.
Hsp90 Inhibitor SNX-7081 dysregulates proteins involved with DNA repair and replication and the cell cycle in human chronic lymphocytic leukemia (CLL) cells.
J Proteome Res. 2013; 12(4):1710-22 [PubMed] Related Publications
The proteomic effects of the Hsp90 inhibitor, SNX-7081, have been determined on the p53-mutated B-cell chronic lymphocytic leukemia (CLL) cell line, MEC1. Following SNX-7081 treatment (500 nM, 24 h), 51 proteins changed abundance by more than 2-fold (p < 0.05); 7 proteins increased while 44 proteins decreased. Proteins identified as differentially abundant by LC-MS/MS were validated by Western blotting (DDB1, PCNA, MCM2, Hsp90, Hsp70, GRP78, PDIA6, HLA-DR). RT-PCR showed that SNX-7081 unexpectedly modulates a number of these proteins in MEC1 cells at the mRNA level (PCNA, MCM2, Nup155, Hsp70, GRP78, PDIA6, and HLA-DR). Pathway analysis determined that 3 of the differentially abundant proteins (cyclin D1, c-Myc and pRb) were functionally related. p53 levels did not change upon SNX-7081 treatment of p53 wild-type Raji cells or p53-mutated MEC1 and U266 cells, indicating that SNX-7081 has a p53-independent mechanism. The decreases in DDB1, MCM2, c-Myc, and PCNA and increases of pRb and cyclin D1 were confirmed in MEC1, U266, Raji, and p53 null HL60 cells by Western blotting. These data suggest that SNX-7081 arrests the cell cycle and inhibits DNA replication and r epair and provides evidence for the mechanism of the observed synergy between Hsp90 inhibitors and drugs that induce DNA strand breaks.

Lin PC, Chiu YL, Banerjee S, et al.
Epigenetic repression of miR-31 disrupts androgen receptor homeostasis and contributes to prostate cancer progression.
Cancer Res. 2013; 73(3):1232-44 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Androgen receptor signaling plays a critical role in prostate cancer pathogenesis. Yet, the regulation of androgen receptor signaling remains elusive. Even with stringent androgen deprivation therapy, androgen receptor signaling persists. Here, our data suggest that there is a complex interaction between the expression of the tumor suppressor miRNA, miR-31, and androgen receptor signaling. We examined primary and metastatic prostate cancer and found that miR-31 expression was reduced as a result of promoter hypermethylation, and importantly, the levels of miR-31 expression were inversely correlated with the aggressiveness of the disease. As the expression of androgen receptor and miR-31 was inversely correlated in the cell lines, our study further suggested that miR-31 and androgen receptor could mutually repress each other. Upregulation of miR-31 effectively suppressed androgen receptor expression through multiple mechanisms and inhibited prostate cancer growth in vivo. Notably, we found that miR-31 targeted androgen receptor directly at a site located in the coding region, which was commonly mutated in prostate cancer. In addition, miR-31 suppressed cell-cycle regulators including E2F1, E2F2, EXO1, FOXM1, and MCM2. Together, our findings suggest a novel androgen receptor regulatory mechanism mediated through miR-31 expression. The downregulation of miR-31 may disrupt cellular homeostasis and contribute to the evolution and progression of prostate cancer. We provide implications for epigenetic treatment and support clinical development of detecting miR-31 promoter methylation as a novel biomarker.

Bagley BN, Keane TM, Maklakova VI, et al.
A dominantly acting murine allele of Mcm4 causes chromosomal abnormalities and promotes tumorigenesis.
PLoS Genet. 2012; 8(11):e1003034 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Here we report the isolation of a murine model for heritable T cell lymphoblastic leukemia/lymphoma (T-ALL) called Spontaneous dominant leukemia (Sdl). Sdl heterozygous mice develop disease with a short latency and high penetrance, while mice homozygous for the mutation die early during embryonic development. Sdl mice exhibit an increase in the frequency of micronucleated reticulocytes, and T-ALLs from Sdl mice harbor small amplifications and deletions, including activating deletions at the Notch1 locus. Using exome sequencing it was determined that Sdl mice harbor a spontaneously acquired mutation in Mcm4 (Mcm4(D573H)). MCM4 is part of the heterohexameric complex of MCM2-7 that is important for licensing of DNA origins prior to S phase and also serves as the core of the replicative helicase that unwinds DNA at replication forks. Previous studies in murine models have discovered that genetic reductions of MCM complex levels promote tumor formation by causing genomic instability. However, Sdl mice possess normal levels of Mcms, and there is no evidence for loss-of-heterozygosity at the Mcm4 locus in Sdl leukemias. Studies in Saccharomyces cerevisiae indicate that the Sdl mutation produces a biologically inactive helicase. Together, these data support a model in which chromosomal abnormalities in Sdl mice result from the ability of MCM4(D573H) to incorporate into MCM complexes and render them inactive. Our studies indicate that dominantly acting alleles of MCMs can be compatible with viability but have dramatic oncogenic consequences by causing chromosomal abnormalities.

Wu C, Zhu J, Zhang X
Integrating gene expression and protein-protein interaction network to prioritize cancer-associated genes.
BMC Bioinformatics. 2012; 13:182 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
BACKGROUND: To understand the roles they play in complex diseases, genes need to be investigated in the networks they are involved in. Integration of gene expression and network data is a promising approach to prioritize disease-associated genes. Some methods have been developed in this field, but the problem is still far from being solved.
RESULTS: In this paper, we developed a method, Networked Gene Prioritizer (NGP), to prioritize cancer-associated genes. Applications on several breast cancer and lung cancer datasets demonstrated that NGP performs better than the existing methods. It provides stable top ranking genes between independent datasets. The top-ranked genes by NGP are enriched in the cancer-associated pathways. The top-ranked genes by NGP-PLK1, MCM2, MCM3, MCM7, MCM10 and SKP2 might coordinate to promote cell cycle related processes in cancer but not normal cells.
CONCLUSIONS: In this paper, we have developed a method named NGP, to prioritize cancer-associated genes. Our results demonstrated that NGP performs better than the existing methods.

de Andrade BA, León JE, Carlos R, et al.
Expression of minichromosome maintenance 2, Ki-67, and geminin in oral nevi and melanoma.
Ann Diagn Pathol. 2013; 17(1):32-6 [PubMed] Related Publications
Evaluation of cell cycle using antibodies against nuclear proteins involved in regulating DNA replication has gained special interest in the effort to predict biologic behavior of benign and malignant tumors. The aim of this study was to analyze the expression of minichromosome maintenance 2, Ki-67, and geminin in oral nevi and melanomas. Expression of these cell proliferation markers was evaluated by immunohistochemistry in 49 oral melanocytic lesions, including 38 intramucosal nevi and 11 primary oral melanomas. The labeling index of each proliferation marker was assessed considering the percentage of cells expressing nuclear positivity out of the total number of cells, counting 1000 cells per slide. Minichromosome maintenance 2, Ki-67, and geminin were rarely expressed in intramucosal nevi, in contrast to oral melanomas, which showed high levels of these cell proliferation markers, particularly minichromosome maintenance 2, indicating it is a more sensitive marker in primary oral melanomas than Ki-67 and geminin. These results indicate that these markers may be involved in the pathogenesis of oral melanomas and could be eventually useful as an additional diagnostic tool for differential diagnosis of oral benign and malignant melanocytic lesions.

Kim SH, Chen G, King AN, et al.
Characterization of vitamin D receptor (VDR) in lung adenocarcinoma.
Lung Cancer. 2012; 77(2):265-71 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
PURPOSE: The anti-proliferative effects of 1α,25-dihydroxyvitamin D(3) (1,25-D(3), calcitriol, the active form of vitamin D) are mediated by the nuclear vitamin D receptor (VDR). In the present study, we characterized VDR expression in lung adenocarcinoma (AC).
EXPERIMENTAL DESIGN: We examined VDR mRNA expression using a quantitative real-time PCR (qRT-PCR) in 100 patients who underwent surgery for lung AC. In a subset of these patients (n=89), we examined VDR protein expression using immunohistochemistry. We also examined the association of VDR protein expression with circulating serum levels of 25-hydroxyvitamin D(3) (25-D(3)) and 1,25-D(3). The antiproliferative effects and cell cycle arrest of 1,25-D(3) were examined using lung cancer cell lines with high (SKLU-1) as well as low (A549) expression of VDR mRNA.
RESULTS: Higher VDR expression correlates with longer survival after adjusting for age, sex, disease stage and tumor grade (HR 0.73, 95% CI 0.58-0.91). In addition, there was a positive correlation (r=0.38) between serum 1,25-D(3) and tumor VDR protein expression. A greater anti-proliferative effect of 1,25-D(3) was observed in high compared to low VDR-expressing cell lines; these effects corresponded to G1 cell cycle arrest; this was associated with a decline in cyclin D1, S-phase kinase protein 2 (Skp2), retinoblastoma (Rb) and minichromosome maintenance 2 (MCM2) proteins involved in S-phase entry.
CONCLUSIONS: Increased VDR expression in lung AC is associated with improved survival. This may relate to a lower proliferative status and G1 arrest in high VDR-expressing tumors.

Nicol AF, Lapa e Silva JR, Cunha CB, et al.
Evaluation of MCM-2 expression in TMA cervical specimens.
PLoS One. 2012; 7(4):e32936 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
BACKGROUND: Minichromosome maintenance proteins (MCM) are highly expressed in actively replicating cells. The need for biological markers for cervical carcinoma and its precursor lesions is emerging. Our main aim was to determine the immunohistochemical expression of MCM-2 in HIV-positive and -negative dysplastic cervical specimens.
METHODS: Immunohistochemical analysis of MCM-2 was performed in a total of 352 cervical TMA specimens of normal control, low-grade CIN, high-grade CIN and invasive tumor. 38 specimens were from HIV-positive women. A receiver operating characteristic (ROC) curve was constructed to determine the best cutoff to diagnose high-grade CIN and invasive cervical cancer.
RESULTS: In the progression from normal epithelium to high-grade CIN and invasive tumor we found significant differences in the MCM-2 expression (p<0.05). Based on the ROC curve of 80% with an area under the curve (AUC) of 0.78, expression of MCM-2 to diagnose high-grade CIN and invasive tumor resulted in sensitivity of 81%, specificity of 66%, a positive predictive value (PPV) of 86% and a negative predictive value (NPV) of 57%. HIV-positive cervices revealed a decreasing expression of MCM-2 in both LGCIN and HGCIN compared with HIV-negative specimens (p<0.0001).
CONCLUSIONS: The present study suggests that immunohistochemical MCM-2 may not be a promising biomarker for diagnosing high-grade CIN and invasive cancer.

Melaiu O, Cristaudo A, Melissari E, et al.
A review of transcriptome studies combined with data mining reveals novel potential markers of malignant pleural mesothelioma.
Mutat Res. 2012 Apr-Jun; 750(2):132-40 [PubMed] Related Publications
Malignant pleural mesothelioma (MPM), a cancer of the serosal pleural cavities, is one of the most aggressive human tumors. In order to identify genes crucial for the onset and progression of MPM, we performed an extensive literature review focused on transcriptome studies (RTS). In this kind of studies a great number of transcripts are analyzed without formulating any a priori hypothesis, thus preventing any bias coming from previously established knowledge that could lead to an over-representation of specific genes. Each study was thoroughly analyzed paying particular attention to: (i) the employed microarray platform, (ii) the number and type of samples, (iii) the fold-change, and (iv) the statistical significance of deregulated genes. We also performed data mining (DM) on MPM using three different tools (Coremine, SNPs3D, and GeneProspector). Results from RTS and DM were compared in order to restrict the number of genes potentially deregulated in MPM. Our main requirement for a gene to be a "mesothelioma gene" (MG) is to be reproducibly deregulated among independent studies and confirmed by DM. A list of MGs was thus produced, including PTGS2, BIRC5, ASS1, JUNB, MCM2, AURKA, FGF2, MKI67, CAV1, SFRP1, CCNB1, CDK4, and MSLN that might represent potential novel biomarkers or therapeutic targets for MPM. Moreover, it was found a sub-group of MGs including ASS1, JUNB, PTGS2, EEF2, SULF1, TOP2A, AURKA, BIRC5, CAV1, IFITM1, PCNA, and PKM2 that could explain, at least in part, the mechanisms of resistance to cisplatin, one first-line chemotherapeutic drug used for the disease. Finally, the pathway analysis showed that co-regulation networks related to the cross-talk between MPM and its micro-environment, in particular involving the adhesion molecules, integrins, and cytokines, might have an important role in MPM. Future studies are warranted to better characterize the role played by these genes in MPM.

Rusiniak ME, Kunnev D, Freeland A, et al.
Mcm2 deficiency results in short deletions allowing high resolution identification of genes contributing to lymphoblastic lymphoma.
Oncogene. 2012; 31(36):4034-44 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Mini-chromosome maintenance (Mcm) proteins are part of the replication-licensing complex that is loaded onto chromatin during the G1-phase of the cell cycle and required for initiation of DNA replication in the subsequent S-phase. Mcm proteins are typically loaded in excess of the number of locations that are used during S-phase. Nonetheless, partial depletion of Mcm proteins leads to cancers and stem cell deficiencies. Mcm2 deficient mice, on a 129Sv genetic background, display a high rate of thymic lymphoblastic lymphoma. Here array comparative genomic hybridization is used to characterize the genetic damage accruing in these tumors. The predominant events are deletions averaging less than 0.5 Mbp, considerably shorter than observed in prior studies using alternative mouse lymphoma models or human tumors. Such deletions facilitate identification of specific genes and pathways responsible for the tumors. Mutations in many genes that have been implicated in human lymphomas are recapitulated in this mouse model. These features, and the fact that the mutation underlying the accelerated genetic damage does not target a specific gene or pathway a priori, are valuable features of this mouse model for identification of tumor suppressor genes. Genes affected in all tumors include Pten, Tcfe2a, Mbd3 and Setd1b. Notch1 and additional genes are affected in subsets of tumors. The high frequency of relatively short deletions is consistent with elevated recombination between nearby stalled replication forks in Mcm2-deficient mice.

Suzuki S, Kurata M, Abe S, et al.
Overexpression of MCM2 in myelodysplastic syndromes: association with bone marrow cell apoptosis and peripheral cytopenia.
Exp Mol Pathol. 2012; 92(1):160-6 [PubMed] Related Publications
Myelodysplastic syndromes (MDS) are characterized by proliferation and apoptosis of bone marrow cells. Minichromosome maintenance protein (MCM) 2, which is known to be essential for regulating DNA replication, has proven to have a pro-apoptotic effect in our recent study. Thus, to determine the role of MCM2 in MDS, real-time PCR, immunohistochemistry and in vitro analysis were performed. Our results showed higher MCM2 expression in MDS than in control and AML. Notably, there was no correlation between MCM2 and Ki67-labeling indices (LIs) in MDS, while MCM2 LIs were significantly correlated with cleaved caspase 3 LIs in MDS. In vitro analysis revealed that MCM2 overexpression induced apoptosis in HL60 cells. Furthermore, MDS bone marrow exhibited higher ratio of MCM2 and cleaved caspase 3 double-positive cells and the ratio was correlated with the degree of leukocytopenia. These results suggest that the up-regulated expression of MCM2 is associated with frequent apoptosis in MDS and may have an important role in the pathogenesis of MDS.

Maschietto M, Piccoli FS, Costa CM, et al.
Gene expression analysis of blastemal component reveals genes associated with relapse mechanism in Wilms tumour.
Eur J Cancer. 2011; 47(18):2715-22 [PubMed] Related Publications
Wilms tumour (WT) is a paediatric kidney tumour, composed of blastemal, epithelial and stromal cells, with a relapse rate of approximately 15%. Long-term survival for patients with relapse remains approximately 50%. Current clinical and molecular research is directed towards identifying prognostic factors to define the minimal and intensive therapy for successful treatment of children with low and high risk of relapse, respectively. Blastemal component presents a high level of aggressiveness and responsiveness to chemotherapy. To identify molecular prognostic markers that are predictive of chemotherapy sensitivity in tumour relapse, blastemal-enriched samples from stage III and IV WT, from patients with relapse or without relapse, were analysed for 4608 human genes immobilised on a customised cDNA platform. These analyses revealed 69 differentially expressed genes, and the top nine genes were further evaluated by qRT-PCR in the initial WT samples. TSPAN3, NCOA6, CDO1, MPP2 and MCM2 were confirmed to be down-regulated in relapse WT, and TSPAN3 and NCOA6 were also validated in an independent sample group. Protein expression of MCM2 and NCOA6 were observed in 38% (13 out of 34) and 28% (9 out of 32), respectively, of independent stage III and IV WT blastema samples, without association with relapse. However, a significant association between MCM2 positive staining and chemotherapy as first treatment suggests the involvement of MCM2 with drug metabolism in WT blastemal cells.

Peng L, Yanjiao M, Ai-guo W, et al.
A fine balance between CCNL1 and TIMP1 contributes to the development of breast cancer cells.
Biochem Biophys Res Commun. 2011; 409(2):344-9 [PubMed] Related Publications
Cyclin L1 (CCNL1) and tissue inhibitor of matrix metalloproteinase-1 (TIMP1) are candidate genes involved in several types of cancer. However, the expression of CCNL1 and the relationship between CCNL1 and TIMP1 in breast cancer cells is unknown. Using patients' breast cancer tissues, the expression of CCNL1 and TIMP1 was measured by cDNA microarray and further confirmed by real-time RT-PCR and western blotting. Overexpression or repression of CCNL1 and TIMP1, individually or together, was performed in breast cancer MDA-MB-231 cells by transient transformation methods to investigate their role in breast cancer cell growth. Simultaneously, mRNA and protein expression levels of CCNL1 and TIMP1 were also measured. CCNL1 and TIMP1 expression was significantly elevated in breast cancer tissues compared with that in peri-breast cancer tissues of patients by cDNA microarray and these results were further confirmed by real-time RT-PCR and western blotting. Interestingly, in vitro experiments showed a stimulatory effect of TIMP1 and an inhibitory effect of CCNL1 on growth of MDA-MB-231 cells. Co-expression or co-repression of these two genes did not affect cell growth. Overexpression of CCNL1 and TIMP1 individually induced overexpression of each other. These data demonstrate that there is a fine balance between CCNL1 and TIMP1, which may contribute to breast cancer development.

Zhao DB, Chandler I, Chen ZM, et al.
Mismatch repair, minichromosome maintenance complex component 2, cyclin A, and transforming growth factor β receptor type II as prognostic factors for colorectal cancer: results of a 10-year prospective study using tissue microarray analysis.
Chin Med J (Engl). 2011; 124(4):483-90 [PubMed] Related Publications
BACKGROUND: The expression of genes encoding a number of pathogenetic pathways involved in colorectal cancer could potentially act as prognostic markers. Large prospective studies are required to establish their relevance to disease prognosis.
METHODS: We investigated the relevance of 19 markers in 790 patients enrolled in a large randomised trial of 5-fluorouracil using immunohistochemistry and chromogenic in situ hybridisation. The relationship between overall 10-year survival and marker status was assessed.
RESULTS: Minichromosome maintenance complex component 2 (MCM2) and cyclin A were significantly associated with overall survival. Elevated MCM2 expression was associated with a better prognosis (HR = 0.63, 95%CI: 0.46 - 0.86). Cyclin A expression above the median predicted an improved patient prognosis (HR = 0.71, 95%CI: 0.53 - 0.95). For mismatch repair deficiency and transforming growth factor β receptor type II (TGFBRII) overexpression there was a borderline association with a poorer prognosis (HR = 0.69, 95%CI: 0.46 - 1.04 and HR = 2.11, 95%CI: 1.02 - 4.40, respectively). No apparent associations were found for other markers.
CONCLUSION: This study identified cell proliferation and cyclin A expression as prognostic indicators of patient outcome in colorectal cancer.

Wu XM, Shao XQ, Meng XX, et al.
Genome-wide analysis of microRNA and mRNA expression signatures in hydroxycamptothecin-resistant gastric cancer cells.
Acta Pharmacol Sin. 2011; 32(2):259-69 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
AIM: To investigate the involvement of microRNAs (miRNAs) in intrinsic drug resistance to hydroxycamptothecin (HCPT) of six gastric cancer cell lines (BGC-823, SGC-7901, MGC-803, HGC-27, NCI-N87, and AGS).
METHODS: A sulforhodamine B (SRB) assay was used to analyze the sensitivity to HCPT of six gastric cancer cell lines. The miRNA and mRNA expression signatures in HCPT-resistant cell lines were then identified using DNA microarrays. Gene ontology and pathway analysis was conducted using GenMAPP2. A combined analysis was used to explore the relationship between the miRNAs and mRNAs.
RESULTS: The sensitivity to HCPT was significantly different among the six cell lines. In the HCPT-resistant gastric cancer cells, the levels of 25 miRNAs were deregulated, including miR-196a, miR-200 family, miR-338, miR-126, miR-31, miR-98, let-7g, and miR-7. Their target genes were related to cancer development, progression and chemosensitivity. Moreover, 307 genes were differentially expressed in HCPT-resistant cell lines, including apoptosis-related genes (BAX, TIAL1), cell division-related genes (MCM2), cell adhesion- or migration-related genes (TIMP2, VSNL1) and checkpoint genes (RAD1). The combined analysis revealed 78 relation pairs between the miRNAs and mRNAs.
CONCLUSION: Hierarchical clustering showed that the miRNA and mRNA signatures in our results were informative for discriminating cell lines with different sensitivities to HCPT. However, there was slightly lower correlation between the expression patterns of the miRNA and those of the predicted target transcripts.

Youns M, Efferth T, Hoheisel JD
Transcript profiling identifies novel key players mediating the growth inhibitory effect of NS-398 on human pancreatic cancer cells.
Eur J Pharmacol. 2011; 650(1):170-7 [PubMed] Related Publications
Pancreatic cancer is one of the most aggressive human malignancies with an increasing incidence worldwide. Despite an increase in the number of systemic treatments available for pancreatic cancer, the impact of therapy on the clinical course of the disease has been modest, underscoring an urgent need for new therapeutic options. Although selective cyclooxygenase-2 inhibitors have been demonstrated to have cancer-preventive effects, the mechanism of their effects is not clearly known. Moreover, there have been no unbiased studies to identify novel molecular targets of NS-398 regarding pancreatic cancer. Here we undertook a gene expression profiling study to identify novel molecular targets modulating the growth inhibitory effects of NS-398 on pancreatic cancer cell lines. Our mRNA-based gene expression results showed that the growth inhibitory effect of NS-398 was accompanied with an activation of G1/S and G2/M cell cycle regulation, P53 signalling, apoptotic, aryl hydrocarbon receptor and death receptor signalling pathways. Moreover, we reported, for the first time, that the growth inhibitory effect of NS-398 is mediated by down-regulation of RRM2, CTGF, MCM2 and PCNA and up-regulation of NAG-1 in all cell lines.

Yang DT, Quann PJ, Petrich AM, et al.
Use of tissue microarray and automated quantitative analysis for screening and validation of potential biomarkers in mantle cell lymphoma.
Appl Immunohistochem Mol Morphol. 2011; 19(1):62-9 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
BACKGROUND: Cancer biomarker studies using the combination of tissue microarray and automated quantitative assessment of immunofluorescence (TMA-AQUA) have been successfully performed for various types of human carcinoma, but its performance characteristics have yet to be evaluated in human lymphoma.
METHODS: A pilot TMA was constructed containing duplicate 1.5 mm cores from 15 cases of mantle cell lymphoma (MCL), 3 cases of low-grade B-cell lymphoma, and 3 cases of benign lymphoid tissue. Protein expression of c-Myc, Cdc2, Cyclin D1, Ki-67, Mcm2, and p27 by immunofluorescence and chromagenic staining were evaluated by AQUA and visual scoring, respectively. Gene expression of cMYC, CDC2, and CCND1 was determined by quantitative nuclease protection assay.
RESULTS: Protein expression between duplicate cores determined by AQUA showed excellent correlation for all markers [correlation coefficient (R)=0.79 to 0.94] and Cyclin D1 expression was significantly higher in MCL cases compared with non-MCL cases (P=0.00019). Overall correlation of AQUA with scoring of chromagenic staining by 2 pathologists was good for all markers (R=0.56 to 0.90), except Cdc2 (R=0.25). Localization of expression to cytoplasmic and/or nuclear compartments was comparable with chromagenic staining patterns for all markers except Ki-67 and Mcm2, where a significant difference between nuclear and cytoplasmic expression could not be appreciated by AQUA, despite clear nuclear localization by chromagenic staining. Correlation of gene expression with protein expression was variable for CDC2, cMYC, and CCND1 (R=0.32, 0.35, and 0.69).
CONCLUSIONS: TMA-AQUA has the potential to be successfully used as a high-throughput protein biomarker screening platform for MCL; however, appropriate target protein selection and antibody performance validation are factors that need to be considered.

Nakahara I, Miyamoto M, Shibata T, et al.
Up-regulation of PSF1 promotes the growth of breast cancer cells.
Genes Cells. 2010; 15(10):1015-24 [PubMed] Related Publications
PSF1 is a subunit of the GINS complex that functions along with the MCM2-7 complex and Cdc45 in eukaryotic DNA replication. Although mammalian PSF1 is predominantly expressed in highly proliferating cells and organs, little is known about the roles of PSF1 in mature cells or cancer cells. We found that PSF1 was expressed at relatively high levels in breast tumor cells, but at low levels in normal breast cells. Knockdown of PSF1 expression using small interfering RNA (siRNA) slowed the growth of breast cancer cell lines by delaying DNA replication but did not affect proliferation of normal human mammary epithelial cells. Reduced PSF1 expression also inhibited anchorage-independent growth in breast cancer cell lines. These results suggest that PSF1 over-expression is specifically involved in breast cancer cell growth. Therefore, PSF1 inhibition might provide new therapeutic approaches for breast cancer.

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