Minichromosome maintenance proteins 2, 3 and 7 in medulloblastoma: overexpression and involvement in regulation of cell migration and invasion

Abstract

Minichromosome maintenance (MCM) proteins 2-7 are important in DNA replication licensing. Functional roles beyond licensing are speculated. In addition, significances in medulloblastoma (MB) remain unclear. In this study, we showed the frequent deregulation of MCM2 and MCM3 expression in 7 MB cell lines and 31 clinical samples. Moreover, DAOY and ONS76 and the clinical samples expressed elevated MCM7 transcripts with genomic gain of the gene. Immunopositivity restricted to tumor cells was found in 41, 37 and 53 out of 73 MB cases for MCM2, MCM3 and MCM7, respectively. High-MCM3 expression was associated with poor prognosis. Knockdowns of these MCMs significantly inhibited anchorage-dependent and -independent MB cell growth. The inhibition of MCM3 expression by small interfering RNA knockdown was related to G1 arrest with reduced cyclin A expression, whereas the MCM2-and MCM7-knocked-down cells arrested at G2/M with increased cyclin A expression. Interestingly, we demonstrated the links of these MCMs with cell migration and invasion using wound-healing and Transwell migration/invasion assays. Exogenous overexpression of MCM2, MCM3 and MCM7 increased anchorage-independent cell growth, and also cell migration and invasion capabilities in MB cells. The knockdown reduced the number of filopodial cells and the cells with intense stress fibers by blocking cdc42 and Rho activation. Taken together, deregulation of MCM2, MCM3 and MCM7 expression might be involved in MB tumorigenesis and we revealed undefined roles of these MCMs in control of MB cell migration and invasion.

Dbf4 and Cdc7 Proteins Promote DNA Replication through Interactions with Distinct Mcm2–7 Protein Subunits

“…For example, roles for both Mcm2-7 and Dbf4/Cdc7 during replication stress have been identified in Xenopus (35,36), and altered abundance of both MCM and DDK subunits have been implicated in human cancers (37,38). The extents to which Dbf4-Mcm2 and Cdc7-Mcm4 interactions are conserved, influence control of DNA replication, and help preserve genome integrity in metazoan organisms are important subjects for future study.…”

Epidemiological and pathological features of primary cardiac tumours in dogs from Poland in 1970–2014

“…Although both Ki-67 and MCM family proteins play a role during cell division and DNA replication, the intensity of their expression in the examined tissues may be diverse Kreuter et al, 2009;Lau et al, 2010;Saydam et al, 2010). Similarly, in this study the expression of three proliferative proteins showed differences, but each examined tumour exhibited a positive reaction for at least one of the above-mentioned markers.…”

“…Recent studies show a high diagnostic potential of beta-catenin and MCM family proteins in the histopathological analysis of various malignant neoplasms (Nowak et al, 2007a,b;Gambichler et al, 2009;Kreuter et al, 2009;Lau et al, 2010;Saydam et al, 2010;Stein et al, 2011;Galofaro et al, 2012). Extension of the examination protocol by MCM family proteins allows a more accurate assessment of the proliferative potential of tumours.…”

“…The results of previous studies suggest that the expression of MCM family proteins can be used as a tool in differentiating between normal and neoplastic tissue (Saydam et al, 2010) or between benign and malignant tumours Kreuter et al, 2009). Lau et al (2010) noted that high MCM-3 expression correlates with poor prognosis in human melanoblastoma. Although the positive expression of all examined proliferation markers noted in the HSAs examined seems promising, the lack of correlation between MCM family proteins and the mitotic index or Ki-67 may suggest that those markers are not useful in the examination of canine HSA.…”

“…Those markers have been examined in recent years on various neoplasms to determine their usefulness as diagnostic and prognostic factors (Nowak et al, 2007a,b;Gambichler et al, 2009;Kreuter et al, 2009;Lau et al, 2010;Saydam et al, 2010;Stein et al, 2011).…”