Down-regulation of SYK by promoter CpG island hypermethylation and its potential role in hepatocellular carcinoma

Abstract

The spleen tyrosine kinase (SYK) has predominantly been studied in hematopoietic cells in which it is involved in immunoreceptor-mediated signaling. However, SYK expression is evidenced in numerous nonhematopoietic cells and its down-regulation has been shown to be involved in tumor formation and progression. Our team has reported that SYK promoter methylation identifies a subset of hepatocellular carcinoma (HCC) with poor prognosis but little is known regarding a biological role of SYK in HCC. We found that SYK promoter methylation is a common event in HCC and is closely associated with its expression. We established stable HCC cell lines that contain SYK gene in inducible expression vector and then compared RNA expression profiles of HCC cell lines with or without induction of SYK. Gene ontology analysis revealed that the SYK-regulated genes are enriched among genes involved in cell adhesion and cell growth. Indeed, we found that SYK increased cell adhesion to fibronectin and decreased cell proliferation. Induced expression of SYK decreased cell migration and invasion by coordination with adhesion molecules as well as suppression of Rho-family GTPases. Our findings suggest that SYK loss is implicated in cell proliferation, migration, and invasion of HCC cells.