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      The Expression and Prognostic Roles of MCMs in Pancreatic Cancer

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          Abstract

          Objectives

          Minichromosome maintenance (MCM) proteins play important roles in DNA replication by interacting with other factors which participate in the regulation of DNA synthesis. Abnormal over-expression of MCMs was observed in numerous malignancies, such as colorectal cancer. However, the expression of MCMs in pancreatic cancer (PC) was less investigated so far. This study was designed to analyze the expression and prognostic roles of MCM1-10 in PC based on the data provided by The Cancer Genome Atlas (TCGA).

          Methods

          Pearson χ 2 test was applied to evaluate the association of MCMs expression with clinicopathologic indicators, and biomarkers for tumor biological behaviors. Kaplan-Meier plots and log-rank tests were used to assess survival analysis, and univariate and multivariate Cox proportional hazard regression models were used to recognize independent prognostic factors.

          Results

          MCM1-10 were generally expressed in PC samples. The levels of some molecules were markedly correlated with that of biomarkers for S phase, proliferation, gemcitabine resistance. And part of these molecules over-expression was significantly associated with indicators of disease progression, such as depth of tumor invasion and lymph node metastasis. Furthermore, MCM2, 4, 6, 8, and 10 over-expression was remarkably associated with shorter disease free survival time, and MCM2, 4,8, and 10 over-expression was associated with shorter overall survival time. Further multivariate analysis suggested that MCM8 was an independent prognostic factor for PC.

          Conclusion

          MCMs abnormal over-expression was significantly associated with PC progression and prognosis. These molecules could be regarded as prognostic and therapeutic biomarkers for PC. The roles of MCMs may be vitally important and the underlying mechanisms need to be furtherinvestigated.

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          Most cited references30

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          A double-hexameric MCM2-7 complex is loaded onto origin DNA during licensing of eukaryotic DNA replication.

          During pre-replication complex (pre-RC) formation, origin recognition complex (ORC), Cdc6, and Cdt1 cooperatively load the 6-subunit mini chromosome maintenance (MCM2-7) complex onto DNA. Loading of MCM2-7 is a prerequisite for DNA licensing that restricts DNA replication to once per cell cycle. During S phase MCM2-7 functions as part of the replicative helicase but within the pre-RC MCM2-7 is inactive. The organization of replicative DNA helicases before and after loading onto DNA has been studied in bacteria and viruses but not eukaryotes and is of major importance for understanding the MCM2-7 loading mechanism and replisome assembly. Lack of an efficient reconstituted pre-RC system has hindered the detailed mechanistic and structural analysis of MCM2-7 loading for a long time. We have reconstituted Saccharomyces cerevisiae pre-RC formation with purified proteins and showed efficient loading of MCM2-7 onto origin DNA in vitro. MCM2-7 loading was found to be dependent on the presence of all pre-RC proteins, origin DNA, and ATP hydrolysis. The quaternary structure of MCM2-7 changes during pre-RC formation: MCM2-7 before loading is a single hexamer in solution but is transformed into a double-hexamer during pre-RC formation. Using electron microscopy (EM), we observed that loaded MCM2-7 encircles DNA. The loaded MCM2-7 complex can slide on DNA, and sliding is not directional. Our results provide key insights into mechanisms of pre-RC formation and have important implications for understanding the role of the MCM2-7 in establishment of bidirectional replication forks.
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            Pancreatic adenocarcinoma.

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              MCM proteins and DNA replication.

              The MCM proteins identify a group of ten conserved factors functioning in the replication of the genomes of archae and eukaryotic organisms. Among these, MCM2-7 proteins are related to each other and form a family of DNA helicases implicated at the initiation step of DNA synthesis. Recently this family expanded by the identification of two additional members that appear to be present only in multicellular organisms, MCM8 and MCM9. The function of MCM8 is distinct from that of MCM2-7 proteins, while the function of MCM9 is unknown. MCM1 and MCM10 are not related to this family, nor to each other, but also function in DNA synthesis.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                3 October 2016
                2016
                : 11
                : 10
                : e0164150
                Affiliations
                [1 ]Pancreas Institute of Nanjing Medical University, Nanjing, 210029, People’s Republic of China
                [2 ]Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of China
                [3 ]Department of General Surgery, The first Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People’s Republic of China
                Saint George's University, UNITED KINGDOM
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: YM.

                • Data curation: YZ.

                • Formal analysis: Y-PP L-DY.

                • Funding acquisition: YM.

                • Investigation: SG.

                • Methodology: Y-PP.

                • Project administration: YM.

                • Resources: YF.

                • Software: YZ.

                • Supervision: YM.

                • Validation: J-JZ.

                • Visualization: J-SW.

                • Writing – original draft: Y-PP.

                • Writing – review & editing: J-SW.

                Article
                PONE-D-16-25819
                10.1371/journal.pone.0164150
                5047525
                27695057
                a8cf7dda-1adf-4452-886f-59f66e47ee39
                © 2016 Peng et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 28 June 2016
                : 20 September 2016
                Page count
                Figures: 2, Tables: 4, Pages: 11
                Funding
                Funded by: the National Natural Science Foundation of China
                Award ID: 81170336
                Award Recipient :
                Funded by: the National Natural Science Foundation of China
                Award ID: the National Natural Science Foundation of China
                Award Recipient :
                Funded by grant numbers: 81170336 and 81272239, website: http://www.nsfc.gov.cn/, full name of the funding institutions: National Natural Science Foundation of China, authors who received the funding: Yi Miao. Dr. Yi Miao designed this study.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Biomarkers
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Cycle and Cell Division
                Synthesis Phase
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Proliferation
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Gastrointestinal Tumors
                Pancreatic Cancer
                Medicine and Health Sciences
                Diagnostic Medicine
                Prognosis
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Cycle and Cell Division
                Biology and Life Sciences
                Genetics
                Gene Expression
                Biology and life sciences
                Genetics
                DNA
                DNA replication
                Biology and life sciences
                Biochemistry
                Nucleic acids
                DNA
                DNA replication
                Custom metadata
                All relevant data applied to perform the analyses in our study was provided in Supporting Information files.

                Uncategorized
                Uncategorized

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