Abstract
Methylation events play a critical role in various cellular processes including regulation of gene transcription and proliferation. Recently, RUNX3 gene, one of TGF-beta-Smads signaling transduction pathway genes, showed strong tumor-suppressor activity by regulation of epithelial proliferation and apoptosis. To elucidate the potential etiological role of the RUNX3 gene in the development of hepatocellular carcinoma (HCC), we have analyzed the methylation status of 5' CpG island of the RUNX3 gene in a series of 73 HCC tissues and 11 liver cell lines. Expectedly, promoter methylation of RUNX3 gene was found in 2 (2.7%) of 73 corresponding normal liver, whereas 30 (41.1%) of 73 HCCs and 4 (40%) of 10 liver cancer cell lines showed hypermethylation of the gene, respectively. There was no significant difference between promoter hypermethylaion and clinicopathologic parameters of primary HCC samples, including histologic grade, microvascular invasion, and clinical stage. Interestingly, demethylating agent 5-aza-2-deoxycytidine induced reactivation and more potent expression of RUNX3 gene in HCC cell lines. Our findings indicate that promoter hypermethylation of RUNX3 gene may occur as an early event in the development of HCC and that methylation may be a major mechanism for inactivation of RUNX3 gene in HCC.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer death in the world, especially in Asian and African
It has been recognized that aberrant hypermethylation of CpG islands in the promoters of certain tumor suppressor genes is known to be associated with transcriptional inactivation and loss of function and that promoter hypermethylation is often an early event in multistep carcinogenesis (Toyota and Issa, 1999; Toyota et al, 1999)
In HCC, methylation associated silencing has been reported in some genes, including APC, GSTP1, p16, COX-2 and E-cadherin, which are involved in hepatocarcinogenesis (Lee et al, 2003)
Summary
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer death in the world, especially in Asian and African. In Korea, it accounts for an estimated 11.2% of all malignancies, with 15.4% in the male population and 6.0% in the female population (Shin et al, 2004). HCC remains a significant contributor to the world’s health burden. It is well known that heavy alcohol intake and infection with the hepatitis B or C virus are important risk factors for HCC. Numerous genetic abnormalities associated with HCC development have been described. Little is known about the molecular genetic event in the development and progression of HCC
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