C-3-01
Identification of genes and pathways involved in DNA
methylation in hepatocellular carcinoma
Sufeiya Subati 10376com@tmd.ac.jp

Takashi Kohda 3
tkohda.epgn@tmd.ac.jp

Kaoru Mogushi 1
mogushi@bioinfo.tmd.ac.jp

Shinji Tanaka 4shinji.msrg@tmd.ac.jp

Mahmut Yasen 2
mahmut@bioinfo.tmd.ac.jp

Hiroshi Tanaka 1
tanaka@bioinfo.tmd.ac.jp

1

Department of System Biology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo,Tokyo 113-8510, Japan2
Department of Pathology, Japanese Foundation for Cancer Research, 3-8-31 Ariake, koto ward,
Tokyo 135-8550, Japan3
Department of Epigenetics, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo,
Tokyo 113-8510, Japan
4
Department of Hepato-Bukuary-Pancreatic Surgery, Tokyo Medical and Dental University,
1-5-45 Yushima, Bunkyo, Tokyo 113-0034, Japan

Keywords: DNA methylation, Hepatocellular carcinoma, DNA microarray
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide.
Despite major efforts to improve diagnosis and treatment of HCC, therapeutic options remain
limited [1] . A role for DNA methylation in the regulation of gene expression was hypothesized many
years ago. Recent genetic studies suggest that tumor suppressor genes (TSGs) are often silenced
during carcinogenesis through epigenetic modification caused by metylation of promoter CpG
island [2] . Therefore, detailed investigation of genes inactivated by DNA methylation in HCC isnecessary for the development of novel treatment options for HCC.
In this study, we aimed to identify candidate genes commonly methylated in HCC. We treatedeight HCC cell lines by the DNA demethylating agent 5 -aza-2'-deoxycytidine (DAC).
Comprehensive gene expression analysis revealed that 489 probe sets had more than two-foldup-regulated in at least six DAC-treated cell lines compared to the control cell lines. Moreover,Gene set enrichment analysis (GSEA) of DAC-treated cells suggested that down-regulation of
immune response pathways were possibly induced by DNA methylation. Interestingly, chemokine(C-X-C motif) ligand 2 (CXCL2) was included in the 44 probe sets and is associated with immune
response. Because immune surveillance is an important host system to inhibit carcinogenesis andthereby down-regulation of CXCL2 might cause immune escape of cancer cells, CXCL2 can beone of the key molecules for cancer progression by DNA methylation.
Our results suggest that these genes and pathways may play an important role incarcinogenesis and disease progress of HCC through inactivation by DNA methylation. Notably,
the candidate gene CXCL2 might be an important molecule for further investigation o f immune
escape in HCC. In our validation studies, we showed that the expression of CXCL2 wasdown-regulated in HCC tissue as compared to non-tumor tissues. In addition, CXCL2 expression
was significantly up-regulated by DAC treatment in HCC cell lines. This suggests that CXCL2
might be an important molecule for further investigation of aberrant methylation in HCC.
References[1] Tischoff I, Tannapfe A. DNA methylation in hepatocellular carcinoma. World J Gastroenterol.
2008;14:1741-8.
[2] Partha M Das and Rakesh Singal. DNA methylation and cancer. Journal of Clinical oncology.
2004;22:4632-42.