Involvement of the Ets-1 gene in overexpression of matrilysin in human hepatocellular carcinoma

Although matrix metalloproteinases (MMPs) are thought to be involved in the invasion and metastasis of a variety of malignant tumors, including human hepatocellular carcinoma (HCC), the mechanisms for the expression of MMPs i n HCC are not known. To understand the mechanism(s) of MMP expression, the expression of matrilysin (MMP-7) and several genes of the Ets transcription factor family was investigated in human HCC and hepatoma-derived cell line s, The role of Ets-l gene expression in HCC was also studied. Analysis by s emiquantitative reverse transcription-PCR revealed that MMP-7 and Ets-l are overexpressed and closely associated in HCC. To clarify the role of Ets-l, hepatoma cells were transduced with human Ets-l or targeted with the Ets-l -specific antisense oligonucleotides, Cells stably transduced with the Ets- l gene showed increased MMP-7 expression compared to parental and mock-tran sfected cells. Cells targeted with Ets-l-specific antisense oligonucleotide s showed reduced expression of MMP-7, Cotransfection of cells with a MMP-7 promoter-reporter gene plasmid and an Ets-l expression vector yielded an in crease in MMP-7 promoter activity in an Ets-l-responsive element-dependent manner. Taken together, these data suggested that the Ets-l oncogene is up- regulated and involved in the overexpression of MMP-7 in human HCC and may contribute to the progression of HCC.