Abstract
BackgroundThe Polo-like Kinase 1 (PLK1) protein regulates cell cycle progression and is overexpressed in many malignant tissues. Overexpression is associated with poor prognosis in several cancer entities, whereby expression of PLK1 shows high inter-individual variability. Although PLK1 is extensively studied, not much is known about the genetic variability of the PLK1 gene. The function of PLK1 and the expression of the corresponding gene could be influenced by genomic variations. Hence, we investigated the gene for functional polymorphisms. Such polymorphisms could be useful to investigate whether PLK1 alters the risk for and the course of cancer and they could have an impact on the response to PLK1 inhibitors.MethodsThe coding region, the 5′ and 3′UTRs and the regulatory regions of PLK1 were systematically sequenced. We determined the allele frequencies and genotype distributions of putatively functional SNPs in 120 Caucasians and analyzed the linkage and haplotype structure using Haploview. The functional analysis included electrophoretic mobility shift assay (EMSA) for detected variants of the silencer and promoter regions and reporter assays for a 3′UTR polymorphism.ResultsFour putatively functional polymorphisms were detected and further analyzed, one in the silencer region (rs57973275), one in the core promoter region (rs16972787), one in intron 3 (rs40076) and one polymorphism in the 3′untranslated region (3′UTR) of PLK1 (rs27770). Alleles of rs27770 display different secondary mRNA structures and showed a distinct allele-dependent difference in mRNA stability with a significantly higher reporter activity of the A allele (p < 0.01).ConclusionThe present study provides evidence that at least one genomic variant of PLK1 has functional properties and influences expression of PLK1. This suggests polymorphisms of the PLK1 gene as an interesting target for further studies that might affect cancer risk, tumor progression as well as the response to PLK1 inhibitors.
Highlights
The Polo-like Kinase 1 (PLK1) protein regulates cell cycle progression and is overexpressed in many malignant tissues
We identified rs27770 as a functional polymorphism that modulates the secondary structure and stability of PLK1 mRNA
Sequencing results of the PLK1 gene and linkage analysis of single nucleotide polymorphisms (SNPs) in regulatory regions Data base analysis and PLK1 sequencing in healthy unrelated Caucasians revealed 49 SNPs with a minor allele
Summary
The Polo-like Kinase 1 (PLK1) protein regulates cell cycle progression and is overexpressed in many malignant tissues. Overexpression is associated with poor prognosis in several cancer entities, whereby expression of PLK1 shows high inter-individual variability. Polo-like kinases (PLKs) belong to the family of serin/ threonin kinases. They are involved in the regulation of cell division and centrosome cycle. Overexpression is associated with poor prognosis in several cancer entities [9,12,13,14,15] Consistent with these findings, different PLK1 inhibitors, i.e. small molecules as well as an siRNA-based formulation, are currently under preclinical and clinical evaluation as promising anticancer drugs [16,17,18]
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