Abstract
Background
Minichromosome maintenance (MCM) proteins are essential components of DNA replication, being related to cell proliferation, and serve as useful biomarkers for cancer screening, surveillance and prognosis. The aim of the present study was to evaluate the clinical significance of MCM-2 and MCM-5 expression in gastric adenocarcinoma in comparison with Ki-67 proliferative marker.
Methods
MCM-2, MCM-5 and Ki-67 expression was assessed immunohistochemically in 66 tumoral samples of gastric adenocarcinoma patients and was statistically analyzed in relation to clinicopathological characteristics and patient survival.
Results
MCM-2 expression did not show significant associations with any clinicopathological parameters, while Ki-67 expression was merely significantly associated with tumor size (P = 0.0150). MCM-2 and Ki-67 expression were more frequently in intestinal (median values: 67.5 and 60%) compared to diffuse-type (median values: 60 and 45%) gastric adenocarcinoma cases without though reaching statistical significance (P > 0.05). MCM-5 expression was significantly associated with tumor size (P = 0.0295), presence of lymph node metastases (P = 0.0216) and tumor histopathological stage (P = 0.0098). Patients presenting high MCM-5 expression had significantly shorter survival times (log-rank test, P = 0.0042), whereas neither MCM-2 nor Ki-67 expression showed significant prognostic value (log-rank test, P = 0.9618 and P = 0.7174, respectively). In multivariate analysis, patient age, histopathological stage and grade of differentiation, but not MCM-5 expression, were identified as independent prognostic factors (Cox regression analysis, P = 0.0097, P = 0.0195, P = 0.0035 and P = 0.3245, respectively).
Conclusions
The present study showed that MCM-5 expression was associated with clinicopathological parameters in gastric adenocarcinoma. However, further studies highlighting the distinct impact of the two histopathological types, intestinal and diffuse, are warranted to delineate whether MCMs could be used as diagnostic and prognostic markers in gastric neoplasia.
Similar content being viewed by others
References
Tye BK. MCM proteins in DNA replication. Annu Rev Biochem. 1999;68:649–686.
Bell SP, Dutta A. DNA replication in eukaryotic cells. Annu Rev Biochem. 2002;71:333–374.
Maiorano D, Lutzmann M, Merchali M. MCM proteins and DNA replication. Curr Opin Cell Biol. 2006;18:130–136.
Takisawa H, Mimura S, Kubota Y. Eukaryotic DNA replication: from-replication complex to initiation complex. Curr Opin Cell Biol. 2000;12:690–696.
Laskey RA, Madine MA. A rotary pumping model for helicase function of MCM proteins at a distance from replication forks. EMBO Rep. 2003;4:26–30.
Tachibana KK, Gonzalez MA, Coleman N. Cell-cycle-dependent regulation of DNA replication and its relevance to cancer pathology. J Pathol. 2005;205:123–129.
Romanowski P, Madine MA. Mechanisms restricting DNA replication to once per cell cycle: the role of Cdc6 and ORC. Trends Cell Biol. 1997;7:9–10.
Endl E, Gerdes J. The Ki-67 protein: fascinating forms and unknown function. Exp Cell Res. 2000;257:231–237.
Bainsh H, Gerdes J. Simultaneous staining of exponentially growing versus plateau phase cells with the proliferation-associated antibody Ki67 and propidium iodide: analysis by flow cytometry. Cell Tissue Kinet. 1987;20:387–391.
Mehrotra P, Gonzalez MA, Johnson SJ, Coleman N, et al. Mcm-2 and Ki-67 have limited potential in preoperative diagnosis of thyroid malignancy. Laryngoscope. 2006;116:1434–1438.
MacCallum DE, Hall PA. The location of pKi67 in the outer dense fibrillary compartment of the nucleolus points to a role in ribosome biogenesis during the cell division cycle. J Pathol. 2000;190:537–544.
Giaginis C, Vgenopoulou S, Vielh P, Theocharis S. MCM proteins as diagnostic and prognostic tumor markers in the clinical setting. Histol Histopathol. 2010;25:351–370.
Freeman A, Morris LS, Mills AD, Stoeber K, et al. Minichromosome maintenance proteins as biological markers of dysplasia and malignancy. Clin Cancer Res. 1999;5:2121–2132.
Toshi L, Bravo R. Changes in cyclin/proliferating cell nuclear antigen distribution during DNA repair synthesis. J Cell Biol. 1988;107:1623–1628.
Ha SA, Shin SM, Namkoong H, Lee H, et al. Cancer-associated expression of minichromosome maintenance 3 gene in several human cancers and its involvement in tumorigenesis. Clin Cancer Res. 2004;10:8386–8395.
Roukos DH. Relevant prognostic factors in gastric cancer. Ann Surg. 2000;232:719–720.
Roukos DH, Kappas AM. Perspectives in the treatment of gastric cancer. Nat Clin Pract Oncol. 2005;2:98–107.
Hohenberger P, Gretschel S. Gastric cancer. Lancet. 2003;362:305–315.
Forman D, Burley VJ. Gastric cancer: global pattern of the disease and an overview of environmental risk factors. Best Pract Res Clin Gastroenterol. 2006;20:633–649.
Tokuyasu N, Shomori K, Nishihara K, Kawaguchi H, et al. Minichromosome maintenance 2 (MCM2) immunoreactivity in stage III human gastric carcinoma: clinicopathological significance. Gastric Cancer. 2008;11:37–46.
Huang HY, Huang WW, Lin CN, Eng HL, et al. Immunohistochemical expression of p16INK4A, Ki-67, and Mcm2 proteins in gastrointestinal stromal tumors: prognostic implications and correlations with risk stratification of NIH consensus criteria. Ann Surg Oncol. 2006;13:1633–1644.
Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. Acta Pathol Microbiol Scand. 1965;64:31–49.
Sobin LH, Wittekind C. TNM classification of malignant tumors. 5th ed. New York: Wiley-Liss; 1997.
Giaginis C, Georgiadou M, Dimakopoulou K, Tsourouflis G, et al. Clinical significance of MCM-2 and MCM-5 expression in colon cancer: association with clinicopathological parameters and tumor proliferative capacity. Dig Dis Sci. 2009;54:282–291.
Giaginis CT, Vgenopoulou S, Tsourouflis GS, Politi EN, Kouraklis GP, Theocharis SE. Expression and clinical significance of focal adhesion kinase in the two distinct histological types, intestinal and diffuse, of human gastric adenocarcinoma. Pathol Oncol Res. 2009;15:173–181.
Theocharis S, Giaginis C, Parasi A, Margeli A, et al. Expression of peroxisome proliferator-activated receptor-gamma in colon cancer: correlation with histopathological parameters, cell cycle-related molecules, and patients’ survival. Dig Dis Sci. 2007;52:2305–2311.
Stoeber K, Tlsty TD, Happerfield L, Thomas GA, et al. DNA replication licensing and human cell proliferation. J Cell Sci. 2001;114:2027–2041.
Lei M. The MCM complex: its role in DNA replication and implications in cancer therapy. Curr Cancer Drug Targets. 2005;5:365–380.
Burger M, Denzinger S, Hartmann A, Wieland W-F, Stoehr R, Obermann EC. Mcm2 predicts recurrence hazard in stage Ta/T1 bladder cancer more accurately than CK20, Ki67 and histological grade. Br J Cancer. 2007;96:1711–1715.
Korkolopoulou P, Givalos N, Saetta A, Goudopoulou A, et al. Minichromosome maintenance proteins 2 and 5 expression in muscle-invasive urothelial cancer: a multivariate survival study including proliferation markers and cell cycle regulators. Hum Pathol. 2005;36:899–907.
Gakiopoulou H, Korkolopoulou P, Levidou G, Thymara I, et al. Minichromosome maintenance proteins 2 and 5 in non-benign epithelial ovarian tumours: relationship with cell cycle regulators and prognostic implications. Br J Cancer. 2007;97:1124–1134.
Murphy N, Ring M, Heffron CC, King B, et al. p16INK4A, CDC6, and MCM5: predictive biomarkers in cervical preinvasive neoplasia and cervical cancer. J Clin Pathol. 2005;58:525–534.
Liu H, Takeuchi S, Moroi Y, Lin N, et al. Expression of minichromosome maintenance 5 protein in proliferative and malignant skin diseases. Int J Dermatol. 2007;46:1171–1176.
Tahara E. Genetic pathways of two types of gastric cancer. IARC Sci Publ. 2004;157:327–349.
Vauhkonen M, Vauhkonen H, Sipponen P. Pathology and molecular biology of gastric cancer. Best Pract Res Clin Gastroenterol. 2006;20:651–674.
Cervantes A, Rodríguez Braun E, Pérez Fidalgo A, Chirivella González I. Molecular biology of gastric cancer. Clin Transl Oncol. 2007;9:208–215.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Giaginis, C., Giagini, A., Tsourouflis, G. et al. MCM-2 and MCM-5 Expression in Gastric Adenocarcinoma: Clinical Significance and Comparison with Ki-67 Proliferative Marker. Dig Dis Sci 56, 777–785 (2011). https://doi.org/10.1007/s10620-010-1348-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10620-010-1348-5