title: Induction of multiple matrix metalloproteinase genes in human hepatocellular carcinoma by hepatocyte growth factor via a transcription factor Ets-1.
abstract: Matrix metalloproteinases (MMPs) have been implicated in progression of hepatocellular carcinoma (HCC), as have hepatocyte growth factor (HGF) and its c-Met receptor. We investigated regulation of MMP gene expression by HGF in human HCC. Expression of mRNAs encoding MMPs, HGF and c-Met receptor was examined by quantitative reverse transcription-polymerase chain reaction (RT-PCR) in human HCC and in five human HCC cell lines. HCC cells were treated with HGF, and mRNA expression for MMPs and Ets-1 which activates transcription of MMPs was investigated. Ets binding activity was determined by gel mobility shift assay. MMP promoter activities were evaluated by reporter gene assay. Effects of Ets-1 antisense oligonucleotides were also examined. At the mRNA level, MMP-1, -3, -7 as well as c-Met were overexpressed in HCC compared with corresponding nonneoplastic liver tissues, although MMP-2, -9 or HGF were not. HGF dose-dependently induced Ets-1 together with an increased Ets binding activity, followed by transcription of MMP-1, -3, and -7. HGF increased MMP promoter activity, as did cotransfection with Ets-1. Ets-1 antisense oligonucleotide transfection down-regulated the MMP expression, and abolished induction by HGF. In conclusion, certain MMPs and c-Met, overexpressed in HCC cells, are induced by HGF via Ets-1. This pathway may contribute to tumor progression.
authors.affiliation: Health Administration Center, Saga Medical School, 5-1-1 Nabeshima, 849-8501, Saga, Japan
authors.forename: Iwata
authors.initials: I
authors.lastname: Ozaki
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Mizuta
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Toru
authors.initials: T
authors.lastname: Yoshimura
authors.forename: Seiji
authors.initials: S
authors.lastname: Kawazoe
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Eguchi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yasutake
authors.forename: Akitaka
authors.initials: A
authors.lastname: Hisatomi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Sakai
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Yamamoto