aberrant methylation of polo-like kinase cpg islands in plk4 heterozygous mice异常甲基化plk4 polo-like激酶cpg岛的杂合的老鼠.pdfVIP

Ward et al. BMC Cancer 2011, 11:71 /1471-2407/11/71 RESEARCH ARTICLE Open Access Aberrant methylation of Polo-like kinase CpG islands in Plk4 heterozygous mice 1 1 2 1* Alejandra Ward , Alan Morettin , David Shum , John W Hudson Abstract Background: Hepatocellular carcinoma (HCC), one of the most common cancers world-wide occurs twice as often in men compared to women. Predisposing conditions such as alcoholism, chronic viral hepatitis, aflatoxin B1 ingestion, and cirrhosis all contribute to the development of HCC. Methods: We used a combination of methylation specific PCR and bisulfite sequencing, qReal-Time PCR (qPCR), and Western blot analysis to examine epigenetic changes for the Polo-like kinases (Plks) during the development of hepatocellular carcinoma (HCC) in Plk4 heterozygous mice and murine embryonic fibroblasts (MEFs). Results: Here we report that the promoter methylation of Plk4 CpG islands increases with age, was more prevalent in males and that Plk4 epigenetic modification and subsequent downregulation of expression was associated with the development of HCC in Plk4 mutant mice. Interestingly, the opposite occurs with another Plk family member, Plk1 which was typically hypermethylated in normal liver tissue but became hypomethylated and upregulated in liver tumours. Furthermore, upon alcohol exposure murine embryonic fibroblasts exhibited increased Plk4 hypermethylation and downregulation along with increased centrosome numbers and multinucleation. Conclusions: These results suggest that aberrant Plk methylation is correlated with the development of HCC in mice. Background (Plk4 +/-) mice develop tumours in comparison to only The Polo-like kinases (Plk