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c‐jun NH 2 ‐terminal kinase pathway is involved in constitutive matrix metalloproteinase‐1 expression in a hepatocellular carcinoma‐derived cell line
Author(s) -
Sugioka Yoshihiko,
Watanabe Tetsu,
Inagaki Yutaka,
Kushida Miwa,
Niioka Maki,
Endo Hitoshi,
Higashiyama Reiichi,
Okazaki Isao
Publication year - 2004
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.20095
Subject(s) - c jun , biology , microbiology and biotechnology , cell culture , transfection , kinase , promoter , transcription factor , cancer research , gene expression , gene , biochemistry , genetics
Abstract Transcription factor c‐Jun serves for cellular proliferation, survival, differentiation and transformation and is recognized as an important factor in cancer development, including hepatocellular carcinoma (HCC). The purpose of present study is to determine the involvement of c‐Jun in matrix metalloproteinase‐1 (MMP‐1) expression, which is previously reported by us to be expressed only in the early stage of human HCC showing stromal invasion. Of 5 human HCC cell lines examined, only HLE cells revealed mRNA and protein expression as well as enzymatic activity of MMP‐1. Transient transfection of an MMP‐1 promoter/luciferase construct (including 4.4 kb full promoter region) into HLE and HCC‐T cells (MMP‐1 nonproducer) showed that high promoter activity was observed only in HLE cells without inducers, and that this promoter activity was still observed when a shorter 0.6 kb proximal promoter construct was transfected. The 0.6 kb promoter region contained 3 AP‐1 sites, and c‐jun mRNA was constitutively expressed in HLE cells without inducers. Furthermore, phosphorylated c‐Jun and c‐Jun NH 2 ‐terminal kinase (JNK) were detected in HLE cells. Promoter activity of the 0.6 kb construct was suppressed with SP600125, a potent inhibitor of JNK, but not with PD98059 and SB203580, potent inhibitors of MEK1/2 and p38, respectively. The inhibitory effect of SP600125 was also observed at protein expression level and in enzymatic activity of MMP‐1. Taken together, this study suggests that the JNK pathway is involved in the expression of MMP‐1 in HCC cells and may represent a new functional role of c‐Jun for HCC development. © 2004 Wiley‐Liss, Inc.