title: H-Ras selectively up-regulates MMP-9 and COX-2 through activation of ERK1/2 and NF-kappaB: an implication for invasive phenotype in rat liver epithelial cells.
abstract: One of the most frequent events in carcinogenesis is uncontrolled activation of Ras signaling pathway. A previous study demonstrated that the introduction of H-Ras into the normal WB-F344 rat liver epithelial (WB) cell line and adult male F344 rats resulted in tumorigenicity. The present study investigated whether H-Ras induced the invasive and migrative phenotypes in WB cells, and subsequently aimed at characterizing the underlying mechanisms. H-Ras induced the invasive and migrative phenotypes of WB cells with a selective up-regulation of matrix metalloproteinase (MMP)-9, but not MMP-2. Cyclooxygenase (COX)-2 and the subsequent production of prostaglandin E2 (PGE2) were also induced by H-Ras. Treatment of H-Ras WB cells with GM6001 and NS398, the inhibitors of MMPs and COX-2, respectively, significantly inhibited the H-Ras-induced invasive and migrative phenotypes. DNA binding activity of nuclear factor (NF)-kappaB, but not that of activator protein (AP)-1, was increased by H-Ras. Caffeic acid phenethyl ester and Bay 11-7082, specific inhibitors of NF-kappaB and IKK, respectively, significantly inhibited the expression of MMP-9 and COX-2, invasion and migration of H-Ras WB cells, revealing NF-kappaB as a transcriptional factor responsible for H-Ras-induced malignant phenotypic conversion of WB cells. Activation of ERKs pathway was critical for H-Ras-induced invasive and migrative phenotypes, up-regulation of MMP-9 and COX-2 as well as enhanced DNA binding activity of NF-kappaB in WB cells. Taken together, these results demonstrate that H-Ras up-regulates MMP-9 and COX-2 through activation of ERKs and IKK-IkappaBalpha-NF-kappaB signal pathway which may contribute to the malignant progression of WB rat liver epithelial cells.
authors.affiliation: Department of Food Biotechnology, School of Agricultural Biotechnology, Seoul National University, Seoul, South Korea.
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.forename: Mi-Sung
authors.initials: MS
authors.lastname: Kim
authors.forename: Nam Joo
authors.initials: NJ
authors.lastname: Kang
authors.forename: Do-Hee
authors.initials: DH
authors.lastname: Kim
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
authors.forename: Hyong Joo
authors.initials: HJ
authors.lastname: Lee
authors.forename: Aree
authors.initials: A
authors.lastname: Moon
mesh_terms: D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D051381:Rats; D015854:Up-Regulation
chemical_list: D016328:NF-kappa B; D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020780:Matrix Metalloproteinase 9; D015689:Oncogene Protein p21(ras)