Induction of multiple matrix metalloproteinase genes in human hepatocellular carcinoma by hepatocyte growth factor via a transcription factor Ets-1.
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.
Ozaki
Iwata
I
Health Administration Center, Saga Medical School, 5-1-1 Nabeshima, 849-8501, Saga, Japan
Mizuta
Toshihiko
T
Zhao
Gang
G
Zhang
Hao
H
Yoshimura
Toru
T
Kawazoe
Seiji
S
Eguchi
Yuichiro
Y
Yasutake
Tsutomu
T
Hisatomi
Akitaka
A
Sakai
Takahiro
T
Yamamoto
Kyosuke
K