Abstract
BackgroundHepatocellular 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.MethodsWe 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).ResultsHere 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.ConclusionsThese results suggest that aberrant Plk methylation is correlated with the development of HCC in mice.
Highlights
Hepatocellular carcinoma (HCC), one of the most common cancers world-wide occurs twice as often in men compared to women
Plk4 is haploinsufficient for tumour suppression, while in humans, loss of heterozygosity (LOH) for the Plk4 gene was found in 60% of a small sample of human hepatocellular carcinomas (HCC) cases [7]
We examined the methylation status of the promoter region of the Polo-like kinases (Plks) genes from DNA extracted from aging mice for normal liver and liver tumours, and detected an increase in methylation status of the Plk4 gene in 22/29 tumours including 16/22 liver tumours studied in male mice (Figure 1a)
Summary
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. The increased rate of tumourigenesis is likely related to the generation of aneuploidy, as altered Plk levels result in abnormal centrosome numbers [8], Plk may play a key role in a DNA damage response pathway consistent with its phosphorylation of p53 [7], and Chk2 [9]. Overexpression of Plk is typically considered to be oncogenic in nature while the remaining Plks likely function as tumour suppressors
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