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Updated: Jan 31, 2026
A "Patient-Like" Orthotopic Syngeneic Mouse Model of Hepatocellular Carcinoma Metastasis
Published on: October 24, 2015
Identification of genes and pathways, including the CXCL2 axis, altered by DNA methylation in hepatocellular
Sophia Subat1,2,3, Kaoru Mogushi1,4, Mahmut Yasen1,3,5
1Department of Systems Biology, Graduate School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan.
Purpose:
Recent genetic studies have suggested that tumor suppressor genes are often silenced during carcinogenesis via epigenetic modification caused by methylation of promoter CpG islands. Here, we characterized genes inactivated by DNA methylation in human hepatocellular carcinoma (HCC) to identify the genes and pathways involved in DNA methylation in hepatocellular carcinoma.
Methods:
Eight HCC-derived cell lines were treated with a DNA demethylating agent, 5-aza-2'-deoxycytidine. Additionally, 100 pairs of primary HCC and adjacent non-cancerous tissues as well as 15 normal liver tissues were analyzed by comprehensive gene expression analysis using microarrays. Moreover, gene set enrichment analysis identified the major molecular pathways associated with DNA methylation. Validation of gene expression and DNA methylation status was performed by real-time PCR after bisulfite modification.
Results:
We showed that CXCL2, an immune-related chemokine, expression was significantly downregulated in tumor tissues and also significantly upregulated by DAC treatment in cell lines. Furthermore, we observed a statistically significant difference in methylation status between normal liver tissues and tumor tissues (P < 0.05). In addition, tumors with higher CXCL2 expression included significantly more numbers of multiple tumors than the lower expression group.
Conclusions:
We identified CXCL2, an immune-related chemokine, decreased in hepatocellular carcinoma and the regulation mechanism may be controlled by methylation. Further studies should be warranted to examine if and to what extent the gene is actually suppressed by methylation and if there is a possibility that the CXCL2 axis plays a role for diagnosis and treatment of hepatocellular carcinoma.
Insights
DNA methylation silences the immune-related chemokine CXCL2 in hepatocellular carcinoma (HCC). This downregulation in HCC tumors suggests CXCL2 may be a target for diagnosis and treatment.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Epigenetic modifications, specifically DNA methylation of promoter CpG islands, are implicated in silencing tumor suppressor genes during carcinogenesis.
- Understanding the specific genes and pathways affected by DNA methylation in hepatocellular carcinoma (HCC) is crucial for identifying novel therapeutic targets.
Purpose of the Study:
- To characterize genes inactivated by DNA methylation in human HCC.
- To identify genes and molecular pathways involved in DNA methylation within HCC.
- To investigate the role of the immune-related chemokine CXCL2 in HCC pathogenesis.
Main Methods:
- Treatment of eight HCC-derived cell lines with the DNA demethylating agent 5-aza-2'-deoxycytidine.
- Comprehensive gene expression analysis using microarrays on 100 primary HCC and adjacent non-cancerous tissue pairs, plus 15 normal liver tissues.
- Gene set enrichment analysis to identify major molecular pathways associated with DNA methylation, with validation by real-time PCR and bisulfite modification.
Main Results:
- CXCL2, an immune-related chemokine, showed significantly downregulated expression in tumor tissues.
- CXCL2 expression was significantly upregulated by DAC treatment in HCC cell lines.
- A statistically significant difference in methylation status was observed between normal liver and tumor tissues (P < 0.05).
- Tumors with higher CXCL2 expression were associated with a higher incidence of multiple tumors.
Conclusions:
- CXCL2 expression is decreased in hepatocellular carcinoma, with its regulation potentially controlled by DNA methylation.
- Further research is warranted to confirm the extent of CXCL2 suppression by methylation.
- The CXCL2 axis may hold potential for the diagnosis and treatment of hepatocellular carcinoma.
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