Quantificational Methylation Analysis of APC and AXIN2 in HBV-related Hepatocellular Carcinoma
Background: Aberrant activation of the Wnt signaling is one of the most common events in hepatocarcinogenesis. The
aim of this study is to investigate the role of methylation modulated APC, AXIN2, APC2 and NKD2 genes expression silencing
in hepatitis B virus (HBV) related heptocellular carcinoma (HCC).
Methods: Eighty paired tumor and adjacent non-tumor tissues were collected from HCC patients with chronic HBV infection
and underlying cirrhosis. The promoter CpG islands (CGI) methylation status of the above genes in paired tissues
and 7 human hepatoma cell lines were quantitatively analyzed. Realtime RT-PCR was performed to determine the mRNA
levels of these genes.
Results: Compared to the adjacent non-tumor tissues, tumor tissues exhibited significantly increased APC hypermethylation
both in frequency (56.2% vs. 78.7%, P = 0.0024) and in intensity (15.0% vs. 34.4%, P < 0.0001). Accordantly, APC
expression in HCC tissues was significantly lower than that in non-tumor tissues (P = 0.0031). AXIN2 CGI hypermethylation
in both non-tumor and tumor tissues were found 91.4% and 85.7% in frequency, and 31.6% and 32.5% in intensity,
both were significantly higher than that in disease-free liver tissues (P = 0.0015 and 0.0008, respectively). Consistent with
the methylation pattern, no statistical difference of the AXIN2 mRNA level between the paired tissues was observed. Intriguingly,
stratified analysis revealed AXIN2 mRNA expression level in tumor tissues was significantly down-regulated
in under 55-year-old male group (P = 0.0138) and lower AXIN2 mRNA expression level in tumor tissues implicated earlier
onset age. In contrary, in over 55-year-old group, tumor tissues’ AXIN2 mRNA level increased in parallel with the increase
of patients age (P = 0.019). No methylation-mediated inactivation of APC2 and NKD2 gene was observed in hepatoma
Conclusion: Our findings suggested that methylation caused APC and AXIN2 expression silencing might be involved in
hepatocarcinogenesis arisen from cirrhotic liver.
Keywords: Hepatocellular Carcinoma (HCC), Hepatitis B Virus (HBV), Methylation, APC, AXIN2.
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