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H‐Ras selectively up‐regulates MMP‐9 and COX‐2 through activation of ERK1/2 and NF‐κB: An implication for invasive phenotype in rat liver epithelial cells
Author(s) -
Lee Ki Won,
Kim MiSung,
Kang Nam Joo,
Kim DoHee,
Surh YoungJoon,
Lee Hyong Joo,
Moon Aree
Publication year - 2006
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.22056
Subject(s) - phenotype , carcinogenesis , matrix metalloproteinase , cancer research , activator (genetics) , prostaglandin e2 , biology , nf κb , cell culture , microbiology and biotechnology , signal transduction , chemistry , endocrinology , gene , biochemistry , genetics
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 E 2 (PGE 2 ) 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)‐κB, 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‐κB and IKK, respectively, significantly inhibited the expression of MMP‐9 and COX‐2, invasion and migration of H‐Ras WB cells, revealing NF‐κB 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‐κB in WB cells. Taken together, these results demonstrate that H‐Ras up‐regulates MMP‐9 and COX‐2 through activation of ERKs and IKK‐IκBα‐NF‐κB signal pathway which may contribute to the malignant progression of WB rat liver epithelial cells. © 2006 Wiley‐Liss, Inc.