Minichromosome Maintenance Family Research Articles

Minichromosome maintenance gene family: potential therapeutic targets and prognostic biomarkers for lung squamous cell carcinoma

The minichromosome maintenance (MCM) gene family comprises of ten members with key roles in eukaryotic DNA replication and are associated with the occurrence and progression of many tumors. However, whether the MCM family contributes to lung squamous cell carcinoma (LUSC) is unclear. In this study, we performed bioinformatic analysis to identify the roles of MCM genes in patients with LUSC. We also evaluated their differential gene expression, prognostic correlation, DNA methylation, functional enrichment of genetic alterations, and immunomodulation. According to the Tumor Immune Estimation Resource database, the expression of MCM2-10 mRNA was elevated in LUSC tissues. According to the Gene Expression Profiling Interactive Analysis database, MCM2-8 and MCM10 were considerably upregulated in LUSC tissues, and protein levels of all MCMs were increased in LUSC tissues. In addition, among the MCM family members, the expression of MCM3 and MCM7 showed the strongest correlation with the prognoses of patients with LUSC. To clarify the role and mechanisms of the MCM family, Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment studies were performed. We detected a significant correlation between the expression patterns of MCM family members and infiltrating immune cells. In conclusion, our results improve the understanding of the aberrant expression of MCM family members in LUSC. These findings demonstrate the potential of the MCM family as therapeutic targets and biomarkers for the diagnosis and prognosis of LUSC.

High-Throughput Screening and Molecular Dynamics Simulation of Natural Products for the Identification of Anticancer Agents against MCM7 Protein.

Minichromosome maintenance complex component 7 (MCM7) belongs to the minichromosome maintenance family that is necessary for the initiation of eukaryotic DNA replication. Overexpression of the MCM7 protein is linked to cellular proliferation and is accountable for critical malignancy in many cancers. Mechanistically, the suppression of MCM7 greatly lowers the cellular proliferation associated with cancer. Advances in immunotherapy have revolutionized treatments for many types of cancer. To date, no effective small molecular candidate has been found that can stop the advancement of cancer produced by the MCM7 protein. Here, we present the findings of methods that used a combination of structure-assisted drug design, high-throughput virtual screening, and simulations studies to swiftly generate lead compounds against MCM7 protein. In the current study, we designed efficient compounds that may combat all emerging cancer targeting the common MCM7 protein. For this objective, a molecular docking and molecular dynamics (MD) simulation-based virtual screening of 29,000 NPASS library was carried out. As a consequence of using specific pharmacological, physiological, and ADMET criteria, four new prevailing compounds, NPA000018, NPA000111, NPA00305, and NPA014826, were successfully selected. The MD simulations were also used for a time period of 50 ns to evaluate for stability and dynamics behavior of the compounds. Eventually, compounds NPA000111 and NPA014826 were found to be highly potent against MCM7 protein. According to our results, the selected compounds may be effective in treating certain cancer subtypes, for which additional follow-up experimental validation is recommended.

An overview on tumor treating fields (TTFields) technology as a new potential subsidiary biophysical treatment for COVID-19.

COVID-19 pandemic situation has affected millions of people with tens of thousands of deaths worldwide. Despite all efforts for finding drugs or vaccines, the key role for the survival of patients is still related to the immune system. Therefore, improving the efficacy and the functionality of the immune system of COVID-19 patients is very crucial. The potential new, non-invasive, FDA-approved biophysical technology that could be considered in this regard is tumor treating fields (TTFields) based on an alternating electric field has great biological effects. TTFields have significant effects in improving the functionality of dendritic cell, and cytotoxic T-cells, and these cells have a major role in defense against viral infection. Hence, applying TTFields could help COVID-19 patients against infection. Additionally, TTFields can reduce viral genomic replication, by reducing the expressions of some of the vital members of DNA replication complex genes from the minichromosome maintenance family (MCMs). These genes not only are involved in DNA replication but it has also been proven that they have a crucial role in viral replication. Also, TTFields suppress the formation of the network of tunneling nanotubes (TNTs) which is knows as filamentous (F)-actin-rich tubular structures. TNTs have a critical role in promoting the spread of viruses through improving viral entry and acting as a protective agent for viral components from immune cells and even pharmaceuticals. Moreover, TTFields enhance autophagy which leads to apoptosis of virally infected cells. Thus, it can be speculated that using TTFields may prove to be a promising approach as a subsidiary treatment of COVID-19.Graphical abstract

Expression and Prognostic Value of MCM Family Genes in Osteosarcoma.

We performed a detailed cancer VS normal analysis to explore the expression and prognostic value of minichromosome maintenance (MCM) proteinsin human sarcoma. The mRNA expression levels of the MCM family genes in sarcoma were analyzed using data from ONCOMINE, GEPIA and CCLE databases. KEGG database was used to analyze the function of MCM2–7 complex in DNA replication and cell cycle. QRT-PCR and western blot were used to confirm the differential expression of key MCMs in osteosarcoma cell lines. Cell Counting Kit-8 and flow cytometry method were used to detect the cell proliferation and apoptosis of hFOB1.19 cells. The results showed that MCM1–7 and MCM10 were all upregulated in sarcoma in ONCOMINE database. MCM2, and MCM4–7 were highly expressed in sarcoma in GEPIA database. Moreover, all these ten factors were highly expressed in sarcoma cell lines. Furthermore, we analyzed the prognostic value of MCMs for sarcoma in GEPIA and found that MCM2, MCM3, MCM4, and MCM10 are prognostic biomarkers for human sarcoma. Analysis results using KEGG datasets showed that MCM4 and MCM6–7 constituted a core structure of MCM2-7 hexamers. We found that AzadC treatment and overexpression of MCM4 significantly promoted hFOB1.19 cell proliferation and inhibited apoptosis. The present study implied that MCM2–4 and 10 are potential biomarkers for the prognosis of sarcoma. The prognostic role of MCM4 may be attributable to the change in its DNA methylation patterns.

Pharmacoinformatics and molecular dynamics simulation-based phytochemical screening of neem plant (Azadiractha indica) against human cancer by targeting MCM7 protein.

Minichromosome maintenance complex component 7 (MCM7) belongs to the minichromosome maintenance family that is important for the initiation of eukaryotic DNA replication. Overexpression of the MCM7 protein is relative to cellular proliferation and responsible for aggressive malignancy in various cancers. Mechanistically, inhibition of MCM7 significantly reduces the cellular proliferation associated with cancer. To date, no effective small molecular candidate has been identified that can block the progression of cancer induced by the MCM7 protein. Therefore, the study has been designed to identify small molecular-like natural drug candidates against aggressive malignancy associated with various cancers by targeting MCM7 protein. To identify potential compounds against the targeted protein a comprehensive in silico drug design including molecular docking, ADME (Absorption, Distribution, Metabolism and Excretion), toxicity, and molecular dynamics (MD) simulation approaches has been applied. Seventy phytochemicals isolated from the neem tree (Azadiractha indica) were retrieved and screened against MCM7 protein by using the molecular docking simulation method, where the top four compounds have been chosen for further evaluation based on their binding affinities. Analysis of ADME and toxicity properties reveals the efficacy and safety of the selected four compounds. To validate the stability of the protein-ligand complex structure MD simulations approach has also been performed to the protein-ligand complex structure, which confirmed the stability of the selected three compounds including CAS ID:105377-74-0, CID:12308716 and CID:10505484 to the binding site of the protein. In the study, a comprehensive data screening process has performed based on the docking, ADMET properties, and MD simulation approaches, which found a good value of the selected four compounds against the targeted MCM7 protein and indicates as a promising and effective human anticancer agent.

Identification of MCM family as potential therapeutic and prognostic targets for hepatocellular carcinoma based on bioinformatics and experiments

AimsThe minichromosome maintenance (MCM) complex is highly conserved, which has drawn increasing attention on physiology and pathology process. However, the role of MCM in hepatocellular carcinoma (HCC) remains largely unclear. We aimed to conduct systematic analysis of expression patterns, prognostic values and potential functions of nine MCM genes in HCC, thus identifying their role in HCC. Main methodsIn our study, we systemically analyzed the role of MCM in prognosis and HCC progression by several bioinformatics analysis tools. Immunohistochemical (IHC) assays were utilized to valid the protein expression of MCM in HCC and in vitro experiments were used to confirm the functions of MCMs in HCC proliferation. Key findingsOverexpression of MCM2-8 and MCM10 were found to be significantly associated with clinical parameters and poor prognosis of HCC patients. The function of MCM was mainly enriched in DNA replication. Moreover, MCM were also associated with several cancer pathway and drug sensitivity in HCC. Close correlations were observed between immune cell infiltration and MCM in HCC. Cell Counting Kit-8 (CCK-8) and clone formation assays suggested the role of MCM2-8 and MCM10 in HCC proliferation. SignificanceThese results have implied that deregulated MCM played an important role in HCC progression and might be considered as potential therapeutic and prognostic targets for HCC.

Comparative genomic analysis reveals evolutionary and structural attributes of MCM gene family in Arabidopsis thaliana and Oryza sativa

The mini-chromosome maintenance (MCM) family, a large and functionally diverse protein family belonging to the AAA+ superfamily, is essential for DNA replication in all eukaryotic organisms. The MCM 2-7 form a hetero-hexameric complex which serves as licensing factor necessary to ensure the proper genomic DNA replication during the S phase of cell cycle. MCM 8-10 are also associated with the DNA replication process though their roles are particularly unclear. In this study, we report an extensive in silico analysis of MCM gene family (MCM 2-10) in Arabidopsis and rice. Comparative analysis of genomic distribution across eukaryotes revealed conservation of core MCMs 2-7 while MCMs 8-10 are absent in some taxa. Domain architecture analysis underlined MCM 2-10 subfamily specific features. Phylogenetic analyses clustered MCMs into 9 clades as per their subfamily. Duplication events are prominent in plant MCM family, however no duplications are observed in Arabidopsis and rice MCMs. Synteny analysis among Arabidopsis thaliana, Oryza sativa, Glycine max and Zea mays MCMs demonstrated orthologous relationships and duplication events. Further, estimation of synonymous and non-synonymous substitution rates illustrated evolution of MCM family under strong constraints. Expression profiling using available microarray data and qRT-PCR revealed differential expression under various stress conditions, hinting at their potential use to develop stress resilient crops. Homology modeling of Arabidopsis and rice MCM 2-7 and detailed comparison with yeast MCMs identified conservation of eukaryotic specific insertions and extensions as compared to archeal MCMs. Protein-protein interaction analysis revealed an extensive network of putative interacting partners mainly involved in DNA replication and repair. The present study provides novel insights into the MCM family in Arabidopsis and rice and identifies unique features, thus opening new perspectives for further targeted analyses.

Identification of mini-chromosome maintenance 8 as a potential prognostic marker and its effects on proliferation and apoptosis in gastric cancer.

Mini‐chromosome maintenance (MCM) proteins play important roles in initiating eukaryotic genome replication. The MCM family of proteins includes several members associated with the development and progression of certain cancers. We performed online data mining to assess the expression of MCMs in gastric cancer (GC) and the correlation between their expression and survival in patients with GC. Notably, MCM8 expression was undoubtedly up‐regulated in GC, and higher expression correlated with shorter overall survival (OS) and progression‐free survival (PFS) in patients with GC. However, the role of MCM8 in GC has not been previously explored. Our in vitro experiments revealed that MCM8 knockdown inhibited cell growth and metastasis. Moreover, MCM8 knockdown induced apoptosis. Mechanistically, the expression levels of Bax and cleaved caspase‐3 were increased, whereas Bcl‐2 expression decreased. Additionally, we demonstrated that MCM8 knockdown suppressed tumorigenesis in vivo. Overall, these results suggest that MCM8 plays a significant role in GC progression.

Huaier Suppresses the Hepatocellular Carcinoma Cell Cycle by Regulating Minichromosome Maintenance Proteins.

PurposeHepatocellular carcinoma (HCC) is a common malignant tumor with limited treatment. Our previous studies demonstrated that Huaier enhanced chemotherapy sensitivity and restrained HCC proliferation. This study aimed to identify differentially expressed proteins with Huaier treatment in HCC cells, providing molecular targets for future targeted therapy of HCC.Materials and MethodsThe effects of Huaier on the cell cycle were determined by flow cytometry and Western blot (WB). Xenograft models were used to verify the effects of Huaier on tumor growth. Then, proteomics was performed to identify the potential proteins regulated by Huaier. The enrichment analysis of GO and KEGG was performed for the differentially expressed proteins. Western blot (WB) and immunohistochemistry (IHC) were used to detect the levels of proteins after Huaier treatment. After that the correlation of differentially expressed proteins with pathological stages was analyzed via the GEPIA database. We also analyzed candidate expression after Huaier treatment in HCC cells by WB and qRT-PCR. Furthermore, siRNA was performed to verify the targeted regulation of Huaier on candidate proteins.ResultsFirst, the proteomics data showed that a total of 160 proteins were identified as differentially expressed proteins, among which six minichromosome maintenance (MCM) family members were enriched in the tumor-associated pathways after Huaier treatment. Moreover, MCM proteins were highly expressed in HCC and closely correlated with the survival of HCC patients. Finally, we confirmed that MCM proteins were targets of Huaier treatment in HCC cells.ConclusionHuaier treatment was closely associated with the activation and inhibition of cancer-related pathways, and the MCM family was identified as a potential target in the antitumor process of Huaier. This study is helpful in understanding the molecular alterations and clinical relevance of HCC after Huaier treatment, which is beneficial for finding new targets and designing effective chemotherapy regimens for the future treatment of HCC.

Elevated expression of minichromosome maintenance 3 indicates poor outcomes and promotes G1/S cell cycle progression, proliferation, migration and invasion in colorectal cancer.

Background: The minichromosome maintenance (MCM) family, a core component of DNA replication, is involved in cell cycle process. Abnormal proliferation has been identified as a crucial process in the evolution of colorectal cancer (CRC). However, the roles of the MCM family in CRC remain largely unknown.Methods: Here, the expression, prognostic significance and functions of the MCM family in CRC were systematically analyzed through a series of online databases including CCLE, Oncomine, HPA, cBioPortal and cancerSEA.Results: We found all MCM family members were highly expressed in CRC, but only elevation of MCM3 expression was associated with poor prognosis of patients with CRC. Further in vitro and in vivo experiments were performed to examine the role of MCM3 in CRC. Analysis of CCLE database and qRT-PCR assay confirmed that MCM3 was overexpressed in CRC cell lines. Moreover, knockdown of MCM3 significantly suppressed transition of G1 to S phase in CRC cells. Furthermore, down-regulation of MCM3 inhibited CRC cell proliferation, migration, invasion and promoted apoptosis.Conclusion: These findings reveal that MCM3 may function as an oncogene and a potential prognosis biomarker. Thus, the association between abnormal expression of MCM3 and the initiation of CRC deserves further exploration.

Crystal structure of the winged-helix domain of MCM8

Minichromosome maintenance 8 (MCM8) is a recently identified member of the minichromosome maintenance family, which possesses helicase and ATPase activity. It interacts with MCM9 and participates in homologous recombination repair. The structure of MCM8 is unclear now. Here, we report the crystal structure of the winged-helix domain of human MCM8 (MCM8-WHD) at 1.21 Å resolution. MCM8-WHD adopts a conserved winged-helix architecture. Structure analysis and biochemical study results showed the DNA binding ability and crucial residues of MCM8-WHD. Our results are helpful to understand the function of MCM8.

Prognostic role of minichromosome maintenance family in multiple myeloma.

Multiple myeloma (MM) is a plasma cell malignancy. The minichromosome maintenance (MCM) family involve in DNA replication and is vital in limiting replication in cell cycle. The prognostic role of MCMs in MM is still unclear. We took four independent GEO datasets to analyze the relationship between the expression of MCMs and myeloma progression and survival. The expression of MCMs showed an upward trend with myeloma progression in 205 patients. High MCM2/3/4/6/8 expression was associated with both poor EFS and OS (all p < 0.050). Multivariate analysis demonstrated that high MCM2 expression, B2M, and LDH were independent risk factors. Moreover, the combination of MCM2/B2M and MCM2/LDH was a better tool in prognostication. In conclusion, high MCM2 expression is an independent adverse prognostic factor and could be used as a prognostic biomarker in MM.

Comprehensive Analysis of Minichromosome Maintenance Family in Human Soft Tissue Sarcoma via Integrated Bioinformatics

Comprehensive Analysis of Minichromosome Maintenance Family in Human Soft Tissue Sarcoma via Integrated Bioinformatics

Comprehensive Analysis of the Expression and Prognosis for MCMs in Human Gastric Cancer.

Purposes:Minichromosome maintenance (MCM) proteins play an important role in replication and cell cycle progression. Even so, their expression and prognostic roles in cancer remain controversial.Methods:To address this issue, the study investigated the roles of MCMs in the prognosis of GC by using ONCOMINE, GEPIA2, UALCAN, Cancer Cell Line Encyclopedia (CCLE), the Human Protein Atlas, Kaplan-Meier Plotter, cBioPortal, GeneMANIA, and DAVID databases.Results:Over expressions of mRNA and cell lines were found in all members of the MCM family, and MCMs were found to be significantly associated with pathological tumor grades in GC patients. Besides, higher mRNA expressions of MCM1/5/7 were found to be significantly associated with shorter overall survival (OS) and progression-free survival (FP) in GC patients, while higher mRNA expression of MCM4/6/9 were connected with favorable OS and FP. Moreover, a high mutation rate of MCMs (68%) was also observed in GC patients.Conclusions:The results indicated that MCM1/5/7 were potential targets of precision therapy for patients with GC. And MCM4/6/9 were new biomarkers for the prognosis of GC. The results of the study will contribute to supplement the existing knowledge, and help to explore therapeutic targets and enhance the accuracy of prognosis for patients with GC.

DNA replication licensing proteins: Saints and sinners in cancer.

DNA replication is all-or-none process in the cell, meaning, once the DNA replication begins it proceeds to completion. Hence, to achieve maximum control of DNA replication, eukaryotic cells employ a multi-subunit initiator protein complex known as "pre-replication complex or DNA replication licensing complex (DNA replication LC). This complex involves multiple proteins which are origin-recognition complex family proteins, cell division cycle-6, chromatin licensing and DNA replication factor 1, and minichromosome maintenance family proteins. Higher-expression of DNA replication LC proteins appears to be an early event during development of cancer since it has been a common hallmark observed in a wide variety of cancers such as oesophageal, laryngeal, pulmonary, mammary, colorectal, renal, urothelial etc. However, the exact mechanisms leading to the abnormally high expression of DNA replication LC have not been clearly deciphered. Increased expression of DNA replication LC leads to licensing and/or firing of multiple origins thereby inducing replication stress and genomic instability. Therapeutic approaches where the reduction in the activity of DNA replication LC was achieved either by siRNA or shRNA techniques, have shown increased sensitivity of cancer cell lines towards the anti-cancer drugs such as cisplatin, 5-Fluorouracil, hydroxyurea etc. Thus, the expression level of DNA replication LC within the cell determines a cell's fate thereby creating a paradox where DNA replication LC acts as both "Saint" and "Sinner". With a potential to increase sensitivity to chemotherapy drugs, DNA replication LC proteins have prospective clinical importance in fighting cancer. Hence, in this review, we will shed light on importance of DNA replication LC with an aim to use DNA replication LC in diagnosis and prognosis of cancer in patients as well as possible therapeutic targets for cancer therapy.

Functional analysis of gene expression profiling-based prediction in bladder cancer.

The present study aimed to analyze the modification of gene expression in bladder cancer (BC) by identifying significant differentially expressed genes (DEGs) and functionally assess them using bioinformatics analysis. To achieve this, two microarray datasets, GSE24152 (which included 10 fresh tumor tissue samples from urothelial bladder carcinoma patients and 7 benign mucosa samples from the bladder), and GSE42089 (which included 10 tissues samples from urothelial cell carcinoma patients and 8 tissues samples from the normal bladder), were downloaded from the Gene Expression Omnibus database for further analysis. Differentially expressed genes (DEGs) were screened between benign the mucosa and control groups in GSE24152 and GSE42089 datasets. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analysis were performed on overlapping DEGs identified in GSE24152 and GSE42089. Protein-protein interaction (PPI) networks and sub-networks were then constructed to identify key genes and main pathways. GO terms analysis was also performed for the selected clusters. In total, 1,325 DEGs in GSE24152 and 647 DEGs in GSE42089 were screened, in which 619 common DEGs were identified. The DEGs were mainly enriched in pathways and GO terms associated with mitotic and chromosome assembly, including nucleosome assembly, spindle checkpoint and DNA replication. In the interaction network, progesterone receptor (PGR), MAF bZIP transcription factor G (MAFG), cell division cycle 6 (CDC6) and members of the minichromosome maintenance family (MCMs) were identified as key genes. Histones were also considered to be significant factors in BC. Nucleosome assembly and sequence-specific DNA binding were the most significant clustered GO terms. In conclusion, the DEGs, including PGR, MAFG, CDC6 and MCMs, and those encoding the core histone family were closely associated with the development of BC via pathways associated with mitotic and chromosome assembly.

Repair of Meiotic DNA Breaks and Homolog Pairing in Mouse Meiosis Requires a Minichromosome Maintenance (MCM) Paralog.

The mammalian Mcm-domain containing 2 (Mcmdc2) gene encodes a protein of unknown function that is homologous to the minichromosome maintenance family of DNA replication licensing and helicase factors. Drosophila melanogaster contains two separate genes, the Mei-MCMs, which appear to have arisen from a single ancestral Mcmdc2 gene. The Mei-MCMs are involved in promoting meiotic crossovers by blocking the anticrossover activity of BLM helicase, a function presumably performed by MSH4 and MSH5 in metazoans. Here, we report that MCMDC2-deficient mice of both sexes are viable but sterile. Males fail to produce spermatozoa, and formation of primordial follicles is disrupted in females. Histology and immunocytological analyses of mutant testes revealed that meiosis is arrested in prophase I, and is characterized by persistent meiotic double-stranded DNA breaks (DSBs), failure of homologous chromosome synapsis and XY body formation, and an absence of crossing over. These phenotypes resembled those of MSH4/5-deficient meiocytes. The data indicate that MCMDC2 is essential for invasion of homologous sequences by RAD51- and DMC1-coated single-stranded DNA filaments, or stabilization of recombination intermediates following strand invasion, both of which are needed to drive stable homolog pairing and DSB repair via recombination in mice.

Using Formal Concept Analysis to Identify Negative Correlations in Gene Expression Data.

Recently, many biological studies reported that two groups of genes tend to show negatively correlated or opposite expression tendency in many biological processes or pathways. The negative correlation between genes may imply an important biological mechanism. In this study, we proposed a FCA-based negative correlation algorithm (NCFCA) that can effectively identify opposite expression tendency between two gene groups in gene expression data. After applying it to expression data of cell cycle-regulated genes in yeast, we found that six minichromosome maintenance family genes showed the opposite changing tendency with eight core histone family genes. Furthermore, we confirmed that the negative correlation expression pattern between these two families may be conserved in the cell cycle. Finally, we discussed the reasons underlying the negative correlation of six minichromosome maintenance (MCM) family genes with eight core histone family genes. Our results revealed that negative correlation is an important and potential mechanism that maintains the balance of biological systems by repressing some genes while inducing others. It can thus provide new understanding of gene expression and regulation, the causes of diseases, etc.

Depletion of minichromosome maintenance protein 7 inhibits glioblastoma multiforme tumor growth in vivo

Minichromosome maintenance (MCM) proteins are key elements that function as a part of the pre-replication complex to initiate DNA replication in eukaryotes. Consistent with their roles in initiating DNA replication, overexpression of MCM family members has been observed in several malignancies. Through bioinformatic analysis of The Cancer Genome Atlas's data on glioblastoma multiforme (GBM), we found that the genomic region containing MCM7 gene was amplified in more than 80% of the present cases. To validate this finding and to identify the possible contribution of the remaining members of the MCM family to GBM progression, we used quantitative real-time PCR to analyze the gene expression profiles of all MCM family members in Grade IV (GBM) tissue samples and observed a significant upregulation in GBM samples compared with normal white matter tissues. In addition, we compared the observed gene expression profiles with those of Grade II and Grade III astrocytoma samples and determined that the observed upregulation was restricted and specific to Grade IV. MCM7 was the most upregulated gene in the gene set we analyzed, and therefore we wanted to identify the role of MCM7 in GBM progression. We determined that siRNA-mediated knockdown of MCM7 expression reduced GBM cell proliferation and also inhibited tumor growth in both xenograft and orthotopic mouse models of GBM. Taken together, our data suggest that MCM7 can be a potential prognostic marker and a novel therapeutic target in GBM therapy.

MCM3 Protein Expression in Follicular and Classical Variants of Papillary Thyroid Carcinoma

Minichromosome maintenance (MCM) proteins are needed as licensors in the DNA replication of eukaryotic cells and transcriptional control of MCM genes has critical role in the regulation of MCM functions. Different MCM protein family members are proposed as diagnostic or prognostic markers in various cancers due to their increased proliferative potential. Among MCM family members, minichromosome maintenance protein 3 (MCM3) expressions in both mRNA and protein levels were shown to be associated with papillary thyroid carcinoma (PTC). But, the usability of MCM3 in some histological variants of PTC might be controversial due to tissue specific molecular heterogeneities. In follicular variant of papillary thyroid carcinoma (FVPTC), a number of genes including MCM3 were shown to be differentially expressed which were specific to this kind of variant. Using immunohistochemistry method, MCM3 protein expression levels were compared in FVPTC, classic variant of papillary thyroid carcinoma (CVPTC), and multi-nodular goiter (MNG) tissues in a group of 32 cases. There was meaningful differences between MNG vs. FVPTC (p = 0.016) and MNG vs. CVPTC (p = 0.019) while there was no significant difference in the comparison FVPTC vs. CVPTC (p = 0.15). Four of the 5 CVPTC cases having surrounding tissue invasion had high expression values. For FVPTC and CVPTC, MCM3 protein expression results were parallel to our previous mRNA expression study while there was downregulation in protein expression despite the increased expression of MCM3 mRNA in MNG suggesting tissue-specific post-transcriptional events in benign thyroid neoplasms of which should be focused on. Moreover, the relatively lower MCM3 protein expression in FVPTC comparing to CVPTC could be due to a different tumorigenic pathway favored in this type of tissue.