A new proliferation marker, minichromosome maintenance protein 2, is associated with tumor aggressiveness in esophageal squamous cell carcinoma

Kato, Hiroyuki; Miyazaki, Tatsuya; Fukai, Yasuyuki; Nakajima, Masahiro; Sohda, Makoto; Takita, Junko; Masuda, Norihiro; Fukuchi, Minoru; Manda, Ryokuhei; Ojima, Hitoshi; Tsukada, Katsuhiko; Asao, Takayuki; Kuwano, Hiroyuki

doi:10.1002/jso.10287

Cited by 57 publications

(55 citation statements)

References 24 publications

(30 reference statements)

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“…Expression of MCM proteins detected by immunohistochemistry predicts survival in patients with breast cancer [27], brain tumours [28,29], non-small cell lung cancer [30,31], prostate cancer [32], bladder [33], oesophageal [34], renal cell [35], and oral squamous cell carcinoma [36]. Consistent with these findings, MCM genes have also been found to be up-regulated at the mRNA level in a range of malignancies by expression microarray analysis.…”

Section: Proteins As Diagnostic Prognostic and Predictive Tumoumentioning

confidence: 62%

Cell‐cycle‐dependent regulation of DNA replication and its relevance to cancer pathology

Tachibana

Gonzalez

Coleman

2005

The Journal of Pathology

140

122

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The highly orchestrated process of DNA replication ensures the accurate inheritance of genetic information from one cell generation to the next. The exact execution of DNA replication depends on a large number of proteins that are being studied extensively in the cell cycle field. Some of these proteins, such as the minichromosome maintenance proteins (MCMs), are essential for the process of DNA replication itself. Others such as geminin are specifically required to limit DNA replication to once per cell cycle. Together, these proteins protect the stability of the human genome in cycling cells. Their expression has been compared with routinely used proliferation markers, such as Ki-67 (MIB-1) and proliferating cell nuclear antigen (PCNA), which fulfil the requirements of molecular tumour markers to varying extents. However, it is with regard to the depth of our understanding of antigen biology that the MCM proteins and geminin qualify exceptionally well as novel cellcycle biomarkers for routine use in clinical practice, particularly in cancer detection and estimation of prognosis. Expression microarray analysis has also independently identified MCMs and their interacting proteins as determinants of the inherent aggressiveness of a wide range of epithelial malignancies.

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Section: Proteins As Diagnostic Prognostic and Predictive Tumoumentioning

confidence: 62%

Cell‐cycle‐dependent regulation of DNA replication and its relevance to cancer pathology

Tachibana

Gonzalez

Coleman

2005

The Journal of Pathology

140

122

View full text Add to dashboard Cite

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“…To date, most studies have focused on MCM2 expression alone. A high level of MCM2 proteins was linked to advanced stages of breast cancer, non-small-cell lung carcinoma, esophageal squamous cell carcinoma, colorectal cancer, gliomas and urothelial carcinoma (Ramnath et al, 2001;Wharton et al, 2001;Rodins et al, 2002;Gonzalez et al, 2003;Kato et al, 2003;Korkolopoulou et al, 2005;Scott et al, 2005;Hanna-Morris et al, 2009). The aberrant expression of MCM2 was also correlated with poor prognosis in patients (Meng et al, 2001;Ramnath et al, 2001;Wharton et al, 2001;Rodins et al, 2002;Korkolopoulou et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2010

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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.

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“…Immunohistochemical studies and expression microarray analyses have independently identified MCM proteins as powerful indicators of worse clinical outcome in various tumour types (Meng et al, 2001;Ramnath et al, 2001;Wharton et al, 2001;Hunt et al, 2002;Rodins et al, 2002;van 't Veer et al, 2002;Gonzalez et al, 2003;Kato et al, 2003;Kodani et al, 2003;Kruger et al, 2003;Rosenwald et al, 2003;Sotiriou et al, 2003;Hashimoto et al, 2004;Neben et al, 2004;Yu et al, 2004a;Korkolopoulou et al, 2005;Shetty et al, 2005). The MCM genes have also appeared as part of 'poor' prognostic signatures in breast cancer (van 't Veer et al, 2002;Sotiriou et al, 2003;Yu et al, 2004a), mantle cell lymphoma (Rosenwald et al, 2003) and medulloblastoma (Neben et al, 2004), whereas in cervical cancer, MCM protein expression appears promising as a predictor of response to radiation therapy (Mukherjee et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Minichromosome maintenance proteins 2 and 5 in non-benign epithelial ovarian tumours: relationship with cell cycle regulators and prognostic implications

et al. 2007

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Minichromosome maintenance proteins (MCM) have recently emerged as novel proliferation markers with prognostic implications in several tumour types. This is the first study investigating MCM-2 and MCM-5 immunohistochemical expression in a series of ovarian adenocarcinomas and low malignant potential (LMP) tumours aiming to determine possible associations with clinicopathological parameters, the conventional proliferation index Ki-67, cell cycle regulators (p53, p27 Kip1 , p21 WAF1 and pRb) and patients' outcome. Immunohistochemistry was applied in a series of 43 cases of ovarian LMP tumours and 85 cases of adenocarcinomas. Survival analysis was restricted to adenocarcinomas. The median MCM-2 and MCM-5 labelling indices (LIs) were significantly higher in adenocarcinomas compared to LMP tumours (Po0.0001 for both associations). In adenocarcinomas, the levels of MCM-2 and MCM-5 increased significantly with advancing tumour stage (P ¼ 0.0052 and P ¼ 0.0180, respectively), whereas both MCM-2 and MCM-5 increased significantly with increasing tumour grade (P ¼ 0.0002 and P ¼ 0.0006, respectively) and the presence of bulky residual disease (Po0.0001 in both relationships). A strong positive correlation was established between MCM-2 or MCM-5 expression level and Ki-67 LI (Po0.0001) as well as p53 protein (P ¼ 0.0038 and P ¼ 0.0500, respectively). Moreover, MCM-2 LI was inversely correlated with p27KipÀ1 LI (P ¼ 0.0068). Finally, both MCM-2 and MCM-5 were associated significantly with adverse patients' outcome in both univariate (X20 vs 420%, P ¼ 0.0011 and X25 vs o25%, P ¼ 0.0100, respectively) and multivariate (P ¼ 0.0001 and 0.0090, respectively) analysis. An adequately powered independent group of 45 patients was used in order to validate our results in univariate survival analysis. In this group, MCM-2 and MCM-5 expression retained their prognostic significance (Po0.0001 in both relationships). In conclusion, MCM-2 and MCM-5 proteins appear to be promising as prognostic markers in patients with ovarian adenocarcinomas.

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A new proliferation marker, minichromosome maintenance protein 2, is associated with tumor aggressiveness in esophageal squamous cell carcinoma

Abstract: MCM2 may be a more reliable and useful marker than Ki-67 in assessing the growth of normal and tumor cells and in evaluating tumor aggressiveness and prognostic value in patients with esophageal SCC.

Cited by 57 publications

References 24 publications

Cell‐cycle‐dependent regulation of DNA replication and its relevance to cancer pathology

Cell‐cycle‐dependent regulation of DNA replication and its relevance to cancer pathology

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

Minichromosome maintenance proteins 2 and 5 in non-benign epithelial ovarian tumours: relationship with cell cycle regulators and prognostic implications

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