Prognostic importance of expression of mini-chromosome maintenance proteins (MCMs) in patients with nasopharyngeal cancer treated with curative radiotherapy

Abstract Objective: The prognostic importance of minichromosome maintenance complex expression in nasopharyngeal cancer is still unknown. We aimed to find whether minichromosome maintenance complex 2-7 expression may potentially be used to predict the prognosis of nasopharyngeal cancer patients treated with definitive radiotherapy. Methods: Between April 2007 and July 2020, patients with nasopharyngeal cancer treated with radiotherapy were identified. Immunohistochemical analysis was performed on formalin-fixed paraffin-embedded tissues of cases. A single pathologist analyzed the histologic specimens of all patients. Results: Totally, 67 patients were included. The median followup was 75.3 months. Higher tumor (T) stage was correlated with minichromosome maintenance complex 2 overexpression. Minichromosome maintenance complex s expression was also associated with histopathologic subgroups. According to univariate analysis, AJCC stage, histopathological subgroups, tumor response after treatment, minichromosome maintenance complex 2, 3, 5, 6 and 7 expression were the prognostic factors that predict overall survival. According to multivariate analysis minichromosome maintenance complex 7 expression was the only prognostic marker for both progression-free survival and overall survival. Conclusion: The overexpression of minichromosome maintenance complex 2, 3, 5, 6 and 7 indicated bad prognosis. Minichromosome maintenance complex 7 was an independent prognostic factor for survival outcomes in nasopharyngeal cancer and may be a potential therapeutic target for treatment.

Expression of minichromosome maintenance protein 6 (MCM6) in colon cancer tissues and its correlation with proliferating cell nuclear antigen (PCNA) / 国际生物医学工程杂志

Objective:To analyze the expression level of minichromosome maintenance protein 6 (MCM6) in colon cancer tissues, the correlation between the expression level of MCM6 and the clinicopathological characteristics of colon cancer patients, and the correlation between MCM6 and PCNA expression.Methods:The expression levels of MCM6 in different tumor tissues were analyzed based on the Human Protein Atlas (HPA) database. The expression levels and correlations of MCM6 and PCNA in colon cancer tissues were analyzed based on The Cancer Genome Atlas (TCGA) database and immunohistochemical experiments. The correlation between MCM6 expression level and clinical characteristics of colon cancer patients was analyzed. The correlation between MCM6 and PCNA expression in colon cancer was analyzed based on TCGA database and Gene Expression Profile Interaction Analysis (GEPIA) database.Results:Bioinformatics analysis and immunohistochemical results confirmed that MCM6 was highly expressed in colon cancer tissues, and its expression level was correlated with the tumor stage of patients ( P=0.01). In colon cancer, the expression of MCM6 and PCNA was correlated with statistical significance ( P<0.05). Conclusions:MCM6 is highly expressed in colon cancer tissue and is related to the clinical characteristics of patients, suggesting that MCM6 can be used as a potential marker of colon cancer.

Expression and clinical significance of minichromosome maintenance protein 3(MCM3) in gastric cancer tissues / 国际生物医学工程杂志

Objective:To study the expression level and clinical significance of minichromosome maintenance protein 3(MCM3) in human gastric cancer.Methods:The expression levels of MCM3 mRNA and protein in gastric cancer and adjacent normal tissues were analyzed using public databases such as TCGA, CCLE and HPA. The clinicopathological features of 69 patients with gastric cancer were retrospectively analyzed, and the expression levels of MCM3 protein in tumor tissues and adjacent normal tissues were detected by immunohistochemical staining, and the relationship between it and clinicopathological features was analyzed. The interaction network of MCM3 proteins was analyzed using the STRING database.Results:The expression levels of MCM3 mRNA and protein in gastric cancer tissues were significantly higher than those in adjacent normal tissues ( P<0.05), and its high expression was correlated with the size of gastric cancer tumors ( P<0.05). In gastric cancer tissue, the expression of MCM3 was correlated with the expression level of proliferating cell nuclear antigen (PCNA) ( R=0.61, P<0.01), and there may be a protein-protein interaction. Conclusions:MCM3 plays an important role in gastric cancer by interacting with PCNA, and it is expected to become a new diagnostic and therapeutic target.

Expression of MCM4/PCNA in gastric cancer and its potential as a potential biomarker / 国际生物医学工程杂志

Objective:To analyze the expressions of minichromosome maintenance protein 4(MCM4) and proliferating cell nuclear antigen (PCNA) in gastric cancer tissues, to explore the relationship between MCM4/PCNA and gastric cancer, and to investigate the possibility of MCM4/PCNA as a potential biomarker for gastric cancer.Methods:Bioinformatics methods were used to analyze the mRNA expressions of MCM4 and PCNA in gastric cancer tissues and adjacent normal tissues. The clinicopathological data of 69 patients with gastric cancer who underwent surgery were retrospectively analyzed. The expression levels of MCM4 and PCNA in gastric cancer tissues and adjacent normal tissues were detected by immunohistochemistry, and their relationship with the clinicopathological characteristics of gastric cancer patients was analyzed.Results:The mRNA levels of MCM4 and PCNA in gastric cancer tissues are significantly higher than those in adjacent normal tissues (all P<0.05). The expression of MCM4 is correlated with the tumor size of gastric cancer ( P=0.037), but there is no significant correlation with gender, age and tumor grade (all P>0.05). Both MCM4 and PCNA proteins are highly expressed in gastric cancer patients. Conclusions:The expression levels of MCM4 and PCNA have a clear correlation with the occurrence of gastric cancer. MCM4 and PCNA are expected to be potential biomarkers for the diagnosis and treatment of gastric cancer.

Expression and Clinical Significance of Minichromosome Maintenance Protein 7 in Sinonasal Squamous Cell Carcinoma / 中国医科大学学报

Objective To investigate the expression of minichromosome maintenance protein 7 (MCM7) in sinonasal squamous cell carcinoma (SNSCC),and evaluate its relationship with tumor differentiation and prognosis of patients.Methods Using immunohistochemistry,MCM7 expression in SNSCC and nasal polyps with chronic sinusitis (NPCRS) were studied,and relationships between markers and clinicapathological features were analyzed.Results In NPCRS,MCM7 positive cells were mainly distributed in the epithelial basal layer and the expression rate was low,whereas in SNSCC,MCM7 positive cells were diffuse and the expression rate was high.MCM7 expression was significantly higher in SNSCC than in NPCRS (P ＜ 0.001) and related to tumor differentiation (P =0.001),increasing gradually with decreasing degree of differentiation.The overall 3-and 5-year survival rates of patients with SNSCC were 61.3％ and 46％,respectively.The 3-year survival rates for patients with stage Ⅰ and Ⅳ were 90％ and 25.6％,respectively,and the 5-year survival rates were 70％ and 17.1％,respectively;the difference was statistically significant (P ＜ 0.001).The 3-and 5-year survival rates of MCM7-negative patients were 36.0％ and 18.0％,respectively,and those of MCM7-positive patients were 59.9％ and 34.2％,respectively;the difference was not statistically significant (P =0.297).Conclusion In SNSCC,MCM7 expression is significantly increased,inversely associated with the degree of tumor differeutiation,and unrelated to the survival rates of patients.

MCM - 2 and Ki - 67 as proliferation markers in renal cell carcinoma: A quantitative and semi - quantitative analysis

ABSTRACT Introduction/Background: Fuhrman nuclear grade is the most important histological parameter to predict prognosis in a patient of renal cell carcinoma (RCC). However, it suffers from inter-observer and intra-observer variation giving rise to need of a parameter that not only correlates with nuclear grade but is also objective and reproducible. Proliferation is the measure of aggressiveness of a tumour and it is strongly correlated with Fuhrman nuclear grade, clinical survival and recurrence in RCC. Ki-67 is conventionally used to assess proliferation. Mini-chromosome maintenance 2 (MCM-2) is a lesser known marker of proliferation and identifies a greater proliferation faction. This study was designed to assess the prognostic significance of MCM-2 by comparing it with Fuhrman nuclear grade and Ki-67. Material and Methods: n=50 cases of various ages, stages, histological subtypes and grades of RCC were selected for this study. Immunohistochemical staining using Ki-67(MIB-1, Mouse monoclonal antibody, Dako) and MCM-2 (Mouse monoclonal antibody, Thermo) was performed on the paraffin embedded blocks in the department of Morbid anatomy and Histopathology, University of Health Sciences, Lahore. Labeling indices (LI) were determined by two pathologists independently using quantitative and semi-quantitative analysis. Statistical analysis was carried out using SPSS 20.0. Kruskall-Wallis test was used to determine a correlation of proliferation markers with grade, and Pearson's correlate was used to determine correlation between the two proliferation markers. Results: Labeling index of MCM-2 (median=24.29%) was found to be much higher than Ki-67(median=13.05%). Both markers were significantly related with grade (p=0.00; Kruskall-Wallis test). LI of MCM-2 was found to correlate significantly with LI of Ki-67(r=0.0934;p=0.01 with Pearson's correlate). Results of semi-quantitative analysis correlated well with quantitative analysis. Conclusion: Both Ki-67 and MCM-2 are markers of proliferation which are closely linked to grade. Therefore, they can act as surrogate markers for grade in a manner that is more objective and reproducible.

Minichromosome Maintenance-2 (MCM2) Expression Differentiates Oral Squamous Cell Carcinoma From Pre-Cancerous Lesions

Background: Proteins necessary for DNA replication and normal regulation for the cell cycle include minichromosome maintenance-2 (Mcm-2). Overexpression of this protein in several premalignant and malignant lesions has been observed. In this study, the diagnostic value of Mcm-2 expression in distinguishing histologically-proven normal oral mucosa (NOM), oral benign keratosis (OBK), oral epithelial dysplasia (OED), and oral squamous cell carcinoma (OSCC) was investigated. Materials and Methods: In this descriptive analytical study, 73 archived specimens of oral tissues, including 20 OBK, 20 OED, 20 OSCC, and 13 NOM cases were selected. The means of labeling indices (LIs) of Mcm-2 expression by immunohistochemistry in each category of lesions were calculated. The data was analyzed by one–way ANOVA, discriminant analysis, and Fisher’s exact tests. Results: The means of labeling indices (LIs) of Mcm-2 expression show statistically significant difference between the four studied groups (P<0.001). Mcm-2 had overexpression and higher positivity in OSCCs. A cut-off point of 67% was determined in order to distinguish OSCC from precancerous lesions. Conclusion: The findings indicated that Mcm-2 could be a useful marker for early detection of oral SCC and dysplasia. Also, due to the overexpression of this marker in OSCC, there exists the possibility of application of Mcm-2 for molecular target therapy in these patients.

Estudo imunoistoquímico de componentes da Via Sonic Hedgehog, Stat3 e Mcm3 em tumores de glândula salivar / Immunohistochemical study components of Via Sonic Hedgehog, Stat3 and MCM3 in salivary gland tumors

O adenoma pleomórfico (AP), o carcinoma mucoepidermóide (CME) e o carcinoma adenóide cístico (CAC) representam tumores frequentes em glândula salivar. A via de sinalização Sonic Hedgehog (Hh) e o Transdutor de sinal e ativador da transcrição 3 (STAT3) desempenham funções importantes na proliferação celular, favorecendo o desenvolvimento tumoral e a proteína MCM3 tem sido considerada uma nova classe de marcadores de proliferação celular. Portanto, o presente trabalho propõe-se a estudar componentes da via Hh, bem como o STAT3 e o MCM3 em neoplasias de glândula salivar, na tentativa de adicionar informações sobre as características biológicas dessas neoplasias. Foram utilizados 9 casos de AP, 17 casos de CAC e 20 casos de CME e, por meio da técnica imunoistoquímica, realizou-se a detecção das seguintes proteínas: SHH, GLI1, SUFU, HHIP, STAT3 e MCM3. No AP, observou-se alta expressão citoplasmática de SHH e SUFU, e baixa expressão de STAT3 e MCM3. No CAC, observou-se alta expressão de GLI1, HHIP e STAT3 e baixa expressão de SHH, SUFU e MCM3. No CME, observou-se alta expressão de SHH, GLI1, SUFU e HHIP e baixa expressão de STAT3 e MCM3. Quando comparado entre os tipos tumorais, observou-se diferença estatisticamente significante para expressão de SHH (p=0.0064), STAT3 (p=0.0003) e MCM3 (p=0.0257)...

The pleomorphic adenoma (PA), mucoepidermoid carcinoma (MEC) and the adenoid cystic carcinoma (ACC) are common tumors arising from salivary glands. The Sonic Hedgehog signaling pathway (Hh) and signal transducer and activator of transcription 3 (STAT3) play important roles in cell proliferation, favoring tumor growth. The MCM3 protein has been considered as a novel class of cell proliferation markers. The aim of this investigation was to study components of the Hh pathway, as well as STAT3 and MCM3 in salivary gland neoplasms in an attempt to add information about the biological characteristics of these neoplasms. We used 9 cases of PA, 17 cases of ACC and 20 cases of MEC. Using immunohistochemistry, were investigated: SHH, GLI1, Sufu, HHIP, STAT3 and MCM3. In PA, there was high expression of cytoplasmic SHH and Sufu, and low expression of STAT3 and MCM3. In the ACC, there was high expression of GLI1, HHIP and STAT3 and low expression of SHH, SUFU and MCM3. In the MEC, we observed high expression of SHH, GLI1, SUFU and HHIP and low expression of STAT3 and MCM3. There was a statistically significant difference between SHH (p=0.0064), STAT3 (p=0.0003) and MCM3 (p=0.0257) when all tumors were compared...

MCM2 and cancers / 国际肿瘤学杂志

Minichromosome maintenance proteins (MCMs) are the primary control factors for eukaryotes DNA replication.MCMs play important roles in the starting place and the extending process of DNA replication.MCM2,one member of MCMs,expresses little in stationary phase while highly in proliferative and transformational phase.MCM2 can accurately reflect the cell proliferation activity and is considered as a specific maker for carcinoma and precancerous lesions.The overexpression of MCM2 is closely correlated with the genesis and development of tumors,and it maybe a good maker for early screening and prognosis assessment in many cancers and used in clinical.

RACK1 promotes the proliferation of lung cancer cells by targeting phosphorylation of MCM7 protein / 肿瘤

Objective: To investigate the effects of gene silencing and overexpression of RACK 1 (receptor for activated C kinase 1) on the proliferation of large-cell lung cancer H460 cells and lung adenocarcinoma A549 cells, and to explore the possible mechanism. Methods: The RACK1 siRNA (small interfering RNA) targeting RACK 1 gene and recombinant vector pCMV-sport6-RACK1 were transfected into both of H460 cells and A549 cells, respectively. MTT method and colony formation assay were used to detect the effect of RACK 1 gene expression on the proliferation of lung cancer cells. Flow cytometry was used to examine the change of cell cycle. The association and interaction of RACK 1 gene expression with the proliferation of lung cancer cells were analyzed by yeast two-hybrid system, co-immunoprecipitation, laser scanning confocal microscopy and co-immunoprecipitation of phosphoproteins. Results: The expression levels of RACK1 protein in the H460 cells and A549 cells were both decreased after transfection with RACK1 siRNA, and the abilities of proliferation and colony-formation were also weakened. The proportion of lung cancer cells arrested at phase S was significantly declined (P <0.01). Meanwhile, the expression level of RACK1 protein was increased after transfection with pCMV-sport6-RACK1, and the abilities of proliferation and colony-formation of lung cancer cells were both strengthened with a prolonged doubling time. The proportion of lung cancer cells arrested at phase S was significantly increased (P <0.01). The results of yeast two-hybrid system and co-immunoprecipitation revealed that RACK1 could directly interact with MCM7 (minichromosome maintenance protein 7). The phosphorylation of MCM7 protein was strengthened through binding to RACK1 which translocated into the cell nucleus. Conclusion: RACK1 promotes the proliferation of lung cancer cells through activating the phosphorylation of MCM7 binding to RACK1. Copyright© 2012 by TUMOR.

Minichromosome maintenance 2 and 5 expressions are increased in the epithelium of hereditary gingival fibromatosis associated with dental abnormalities

INTRODUCTION: Gingiva fibromatosis is a relatively rare condition characterized by diffuse enlargement of the gingiva, which is caused by expansion and accumulation of the connective tissue. OBJECTIVE: The aim of the present study was to investigate proliferative and apoptotic biomarker expression in normal gingiva and two forms of gingival fibromatosis. METHODS: Archived tissue specimens of hereditary gingival fibromatosis, gingival fibromatosis and dental abnormality syndrome and normal gingiva were subject to morphological analysis and immunohistochemical staining. The results were analyzed statistically. RESULTS: Proteins associated with proliferation were found in the nuclei of epithelial cells from the basal and suprabasal layers, whereas apoptotic proteins were detected in the cytoplasm of the upper layers of the epithelium. Increased expressions of minichromosome maintenance proteins 2 and 5 were observed in the gingival fibromatosis and dental abnormality syndrome samples. In contrast, geminin expression was higher in normal gingiva samples. No difference in the expression of apoptotic proteins was observed among the groups. CONCLUSION: Our findings support a role for augmented proliferation of epithelial cells within the overgrown tissues associated with gingival fibromatosis or dental abnormality syndrome. However, our data suggest that different biological mechanisms may account for the pathogenesis of different types of gingival fibromatosis.

Minichromosome maintenance proteins and cancer / 国际肿瘤学杂志

Minichromosome maintenance proteins are novel cell proliferation markers. These proteins have demonstrated clinical values in cancer diagnosis, prognosis, and screening, and have shown promising potentials in targeted treatments of cancer.

MCM3AP, a Novel HBV Integration Site in Hepatocellular Carcinoma and Its Implication in Hepatocarcinogenesis / 华中科技大学学报（医学）（英德文版）

A novel HBV integration site involved in hepatocarcinogenesis was investigated. The HBV DNA integration sites were detected by Alu-PCR in hepatocellular carcinoma tissues, matched surrounding liver tissues in 30 patients with hepatitis B-related hepatocellular carcinoma (HCC) and 3 cases of normal liver tissues. The integration sites and flanking sequences in human genome were sequenced and blasted, and the expression of integrated HBV genes was determined by reverse tran-scriptase-polymerase chain reaction (RT-PCR). The influence of the up-regulated expression of inte-grated genes on hepatocarcinogenesis was analyzed. Nineteen integration sites of HBV DNA into HCC tissues were obtained by RT-PCR and sequencing. These genes encoding proteins were: LOC51030, LOC 157777, minichromosome maintenance complex component 3 associated protein (MCM3AP), MCTP1, SH3 and multiple ankyrin repeat domains 2 isoform 2, CCDC40, similar to HCG2033532, mitochondrial ribosomal S5 pseudogene 4. One of them was integrated into the intron of MCM3AP. RT-PCR demonstrated that the expression levels of MCM3AP mRNA in HCC tissues, matched surrounding liver tissues and normal liver tissues were in a descendent order. The ratio of MCM3AP mRNA to the GAPDH mRNA in these three tissues was 1.07375, 0.21573, 0.06747 re-spectively, with the difference being statistically significant among them (P<0.05). Meanwhile, the expression levels of MCM3AP mRNA from HCC tissues in which HBV DNA integrated into MCM3AP were still significantly higher than those without HBV DNA integrated into MCM3AP. It was concluded that the HBV DNA integration sites into human genome were random, and MCM3AP was a new site. The up-regulated MCM3AP mRNA may affect flanking sequences which promote the hepatocarcinogenesis.

Expressions and clinicopathological significance of MCM5 and E2F-1 in patients with gastric carcinoma / 中国现代普通外科进展

Objective:To explore the relationship between the expressions of MCM5 and E2F-1 with the genesis,clinicopathological parameters of gastric carcinoma.Methods:Immunohistochemistry SP method was used to detect the expressions of MCM5 and E2F-1 in gastric car- cinoma tissues of 57 cases and in normal gastric mucosa of 20 cases.The correlation between expressions of MCM5 and E2F-1 and clinicopathological parameters of gastric carcinoma was analysed. Results:The positive expression rate of MCM5 in cancer tissues was 71.9%(41/57),while in normal mucosa it was 0(0/20).The difference between the two groups was statistically significant (P0.05).The correlation between MCM5 and E2F-1 expressions in gastric carcinoma was highly significant positive(r=0.635,P=0.000).Conclusion: Overexpression of MCM5 and E2F-1 corelates with occurence and development of gastric carcinoma.MCM5 and E2F-1 may work in the early phase in carcinogenesis of gastric carcinoma.

Using MCM2 as A Novel Cell Replication Marker in Diagnosing Colorectal Carcinoma / 中国普外基础与临床杂志

Objective To study the current research status of minichromosome maintenance protein 2 (MCM2), the cell cycle proliferation marker, in the diagnosis of colorectal carcinoma. Methods Literatures about the application of MCM2 in the study of colorectal carcinoma were collected and reviewed.Results MCM2, as a marker of cell dysplasia and malignancy, was usually used in the study of carcinoma. The study on expression of MCM2 in the cell of colorectum in different proliferational stage might help to screen colorectal carcinoma as early as possible. Conclusion As a relatively specific and sensitive marker of cell proliferation, MCM2 might become a promising mark for diagnosing colorectal carcinoma in the early stage.

Diagnosis of bladder cancer by detection of survivin and minichromosome maintenance 5 protein in urine sediments / 中华泌尿外科杂志

0.05). Conclusions The detections of survivin and MCM5 in urine sediments are sensitive and non-invasive diagnostic tests for bladder cancer.The combination of survivin and MCM5 may be more effective than either of them alone.

Expression of MCM4 and CDC6 in uterine cervical carcinoma and its relation with HPV_(16/18) infection / 中国肿瘤生物治疗杂志

Objective:To investigate the expression of minichromosome maintenance proteins 4(MCM4)and cell division cycle 6(CDC6)in uterine cervical carcinomas and its relationship with human papilloma virus(HPV)16/18 infection.Methods:The expression of MCM4 and CDC6 was examined in 50 squamous cell carcinoma specimens,20 cervical intraepithelial neoplasia(CIN)Ⅱ-Ⅲ specimens,20 CINⅠ specimens,and 20 normal cervical tissues by immunohistochemical method.The infections of HPV type 16,18 DNA were determined by PCR.Results:(1)The expression of MCM4 and CDC6 in uterine cervical carcinoma tissues was significantly higher than that in the CIN specimens and normal cervical tissues(Both P0.05).(2)The positive rates of(HPV)16/18 were significant different between cervical carcinomas,CIN and normal tissues(P0.05).(3)MCM4 expression were positively correlated with the expression of CDC6 in uterine cervical carcimonas(r=0.390,P

Expression and clinical significance of Rb gene and MCM2 in prostate cancer / 重庆医科大学学报

Objective: To study the expression of retinoblastoma susceptibility gene(Rb) and minichromosome maintenance protein 2(MCM2) in primary prostate cancer(PCa) and its clinical significance.Methods: The expression of MCM2 protein and pRb were detected in 49 cases of PCa,20 cases of benign prostate hyperplasia(BPH),10 cases of normal prostate tissues(NP) by EliVisionTM plus immunohistochemical staining.Results: The positive expression rate of pRb in PCa,BPH,NP were 44.90%,80% and 90% respectively.The expression level of pRb in PCa was significantly lower than that in BPH(P

Expression of Mcm2 protein in colorectal neoplasm / 第二军医大学学报

Objective:To determine the expression of Mcm2(a member of MCMs family) in colorectal neoplasm and to assess the relationship between Mcm2 expression and clinicopathological characteristics of colorectal neoplasm.Methods: Immunohistochemical staining was used to detect the expression of Mcm2 in normal colorectal mucosa(n=23),adenoma(n=33),and cancer(n=69) tissues,and the results were quantified by calculating the labelling index(LI).Results: Mcm2 expression in normal colorectal mucosa was confined to the 1/3-1/2 of colonic crypts basal;there was no expression in coloncytes surface.In colorectal adenoma and cancer,Mcm2 expression was seen throughout epithelium,including the coloncytes surface.The median(range) LI of Mcm2 in these 3 tissues were 18%(5%-37%),35%(15%-75%),66%(41%-90%),respectively.The differences between normal mucosa,adenoma and cancer were statistically significant(P