Epigenetic upregulation of HGF and c-Met drives metastasis in hepatocellular carcinoma

• Published in: PloS one 2013-05, Vol.8 (5), p.e63765
• Main Authors: Ogunwobi, Olorunseun O, Puszyk, William, Dong, Hui-Jia, Liu, Chen
• Format: Article
• Language: English
• Subjects: Abdomen; Animals; Base Sequence; Biology; Blood circulation; c-Met protein; Carcinogenesis - genetics; Carcinogenesis - pathology; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell culture; Cell Line, Tumor; CpG islands; Demethylation; Deoxyribonucleic acid; DNA; DNA methylation; DNA Methylation - genetics; Epigenesis, Genetic; Epigenetics; Epithelial-Mesenchymal Transition - genetics; Gene Expression Regulation, Neoplastic; Hepatocellular carcinoma; Hepatocyte growth factor; Hepatocyte Growth Factor - genetics; Hepatocytes; Hepatology; Humans; Immunology; Laboratories; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Medical prognosis; Medical research; Medicine; Mesenchyme; Mesoderm - pathology; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Models, Biological; Molecular Sequence Data; Mortality; Neoplastic Cells, Circulating - metabolism; Neoplastic Cells, Circulating - pathology; Pathology; Peripheral blood; Promoter Regions, Genetic - genetics; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; Regulators; Studies; Therapeutic applications; Tumor cell lines; Tumor cells; Tumorigenicity; Up-regulation; Up-Regulation - genetics
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0063765

Hepatocyte growth factor (HGF) and its receptor, c-Met, are important regulators of growth and differentiation of healthy hepatocytes. However, upregulation of HGF and c-Met have been associated with tumor progression and metastasis in hepatocellular carcinoma (HCC). Hematogenous dissemination is the most common route for cancer metastasis, but the role of HGF and c-Met in circulating tumor cells (CTCs) is unknown. We have isolated and established a circulating tumor cell line from the peripheral blood of a mouse HCC model. Our studies show that these CTCs have increased expression of HGF and c-Met in comparison to the primary tumor cells. The CTCs display phenotypic evidence of epithelial-mesenchymal transition (EMT) and the EMT appears to be inducible by HGF. Epigenetic analysis of the c-Met promoter identified significant loss of DNA methylation in CTCs which correlated with overexpression of c-Met and increased expression of HGF. Six specific CpG sites of c-Met promoter demethylation were identified. CTCs show significantly increased tumorigenicity and metastatic potential in a novel orthotopic syngeneic model of metastatic HCC. We conclude that during hematogenous dissemination in HCC, CTCs undergo EMT under the influence of increased HGF. This process also involves up regulation of c-Met via promoter demethylation at 6 CpG sites. Consequently, targeting HGF and c-Met expression by CTCs may be a novel non-invasive approach with potential clinical applications in HCC management.