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

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 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)-jB, 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-jB and IKK, respectively, significantly inhibited the expression of MMP-9 and COX-2, invasion and migration of H-Ras WB cells, revealing NF-jB as a transcriptional factor responsible for HRas-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-jB in WB cells. Taken together, these results demonstrate that H-Ras up-regulates MMP-9 and COX-2 through activation of ERKs and IKK-IjBa-NF-jB signal pathway which may contribute to the malignant progression of WB rat liver epithelial cells. ' 2006 Wiley-Liss, Inc.

The Effect of Ras Inhibition on the Proliferation, Apoptosis and Matrix Metalloproteases Activity in Rat Hepatic Stellate Cells

“…MMPs, such as MMP-2 and MMP-9, display strong activity in tumor cells transformed by Ras [27][28][29]. Contrary to our results, inhibition of Ras by a farnesyltransferase inhibitor reduced levels of secreted MMP-2 and MMP-9 in prostate cancer cells [30].…”

Loss of p53 and MCT-1 Overexpression Synergistically Promote Chromosome Instability and Tumorigenicity

“…MCT-1 overexpression itself may be not only directly oncogenic but could also induce a constellation of invasive and metastatic factors (e.g., HIF-1α, MMP-9, and integrin β4) by its transcriptional or translational regulation function. The enhancing H-Ras gene expression followed by an extremely active Ras-MEK-MAPK signaling cascade reinforces tumorigenic outcomes and angiogenic effects (18,19,32). Oncogenic MCT-1 participates in stimulating the Ras-MEK-MAPK cascade ( Fig.…”

“…Several studies have indicated that activation of MAPK signaling is important for cell transformation and genomic destabilization, which are induced by many oncoproteins, including Mos, Ras, and Raf (15)(16)(17). Furthermore, activating MAPK (ERK1/2) and H-Ras selectively induces cell invasive phenotypes by enhancing matrix metalloproteinase-9 (MMP-9) and cyclooxygenase-2 expression along with increasing invasion and migration abilities (18,19). The chromosome instability caused by p53 deficiency can be enhanced to a greater extent by the constitutively active MAPK pathway.…”

Simvastatin inhibits induction of matrix metalloproteinase-9 in rat alveolar macrophages exposed to cigarette smoke extract

“…Moreover, RAS (Moon et al, 2004;Lee et al, 2006) and Rho proteins (Turner et al, 2005) are related to MMP-9 expression. Accordingly, we investigated whether simvastatin could suppress CSE-mediated MMP-9 induction via the inhibition of protein prenylation.…”