Abstract
Minichromosome Maintenance (MCM) proteins play important roles in cell cycle progression by mediating DNA replication initiation and elongation. Among 10 MCM homologues MCM 2–7 form a hexamer and assemble to the pre-replication complex acting as replication licensing factors. Binding and function of MCM2-7 to pre-replication complex is regulated by MCM10 mediated binding of RECQL4 with MCM2-7. The purpose of this study is to explore the role of MCMs in cervical cancer and their correlation with the clinical parameters of cervical cancer. We have investigated sixty primary cervical cancer tissue samples, eight cervical cancer cell lines and thirty hysterectomised normal cervical tissue. The expression profiling of MCMs was done using semi-quantitative RT-PCR, immunoblotting and immunohistochemistry. MCM2, 4, 5, 6, 7, 10 and RECQL4 are significantly over-expressed in cervical cancer. Among these, MCM4, 6 and 10 show increased frequency of over expression along with advancement of tumor stages. MCM4, 5 and 6 also show differential expression in different types of lesion, while MCM2 and MCM10 are over expressed in cervical cancer irrespective of clinico-pathological parameters. Our data indicates the role of MCM4, MCM5, MCM6, MCM10 and RECQL4 in the progression of cervical cancer.
Highlights
DNA replication is the event of common interest in the study of initiation and progression of cancer
Our semi-quantitative RT-PCR analysis of MCM2-7, MCM10 and RECQL4 in primary tumors and CC cell lines reveals that MCM2, MCM4, MCM5, MCM6, MCM10 and RECQL4 are frequently up-regulated in primary tumors and CC cell lines, while MCM3 does not show significant change
MCM2 shows significant up regulation (p = 0.0001) in primary tumor (n = 60, 0.77760.425, median = 0.75, p = 0.0001) and cell lines (n = 8, 0.55260.176, median = 0.58, p = 0.0001) compared to normal (n = 30, 0.11860.138, median = 0.06) (Figure 1A)
Summary
DNA replication is the event of common interest in the study of initiation and progression of cancer. A normal cell maintains its entry and exit into cell cycle by several checkpoints and ‘‘licensing’’ its DNA replication only once per cell cycle This licensing mechanism includes the formation of pre-replication complexes (pre-RCs) in late M and early G1 phases and their subsequent activation at the G1–S boundary. At the G1–S transition, the activity of two kinases, CDC7 and cyclins E/A-CDK2, recruit additional factors to pre-RCs, resulting in the formation of pre-initiation complexes (pre-ICs) [3]. CDC7 and CDK2 activate the MCM2–7 helicases, which together with formation of pre-IC result in recruitment of DNA polymerases and initiation of DNA replication. During late S and M phases, high activity of cyclin-dependent kinase (CDK) results in dissolution of the pre-RCs and destruction of selective pre-RC components, thereby preventing DNA re-replication [4]
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