Abstract |
Collagenase-1 [ matrix metalloproteinase ( MMP)-1] is expressed by stromal fibroblasts of various invasive malignant tumors. Here, we have examined the molecular mechanisms of tumor-induced expression of MMP-1 by stromal fibroblasts. Treatment of fibroblasts with conditioned media of tumor cells derived from squamous cell carcinomas (SCCs) of the oral cavity and larynx resulted in activation of fibroblast MMP-1 expression at the transcriptional level. The induction of MMP-1 expression correlates with activation of c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase and phosphorylation of c-Jun and activating transcription factor-2 (ATF-2) and is dependent on the activity of p38 mitogen-activated protein kinase. Furthermore, using fibroblasts derived from JNK2-/- mice, we show that JNK2 is required for induction of fibroblast collagenase-3 expression in response to conditioned SCC tumor cell medium. Together, these results provide evidence that stress-activated p38 and JNK pathways play a crucial role in paracrine regulation of collagenolytic capacity of stromal fibroblasts in SCCs and suggest JNK2 as a novel target for inhibition of MMP-1 expression and tumor invasion.
|
Authors | J Westermarck, S Li, P Jaakkola, T Kallunki, R Grénman, V M Kähäri |
Journal | Cancer research
(Cancer Res)
Vol. 60
Issue 24
Pg. 7156-62
(Dec 15 2000)
ISSN: 0008-5472 [Print] United States |
PMID | 11156425
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- ATF2 protein, human
- Activating Transcription Factor 2
- Atf2 protein, mouse
- Cyclic AMP Response Element-Binding Protein
- Proto-Oncogene Proteins c-fos
- Proto-Oncogene Proteins c-jun
- Recombinant Proteins
- Transcription Factors
- RNA
- Mitogen-Activated Protein Kinase 9
- Mitogen-Activated Protein Kinases
- p38 Mitogen-Activated Protein Kinases
- Collagenases
- MMP13 protein, human
- Matrix Metalloproteinase 13
- Mmp13 protein, mouse
- collagenase 1
- Matrix Metalloproteinase 1
|
Topics |
- Activating Transcription Factor 2
- Animals
- Blotting, Northern
- Carcinoma, Squamous Cell
(enzymology)
- Cells, Cultured
- Collagenases
(metabolism)
- Cyclic AMP Response Element-Binding Protein
(metabolism)
- Enzyme Activation
- Fibroblasts
(enzymology)
- Head and Neck Neoplasms
(metabolism)
- Humans
- Infant, Newborn
- Laryngeal Neoplasms
(enzymology)
- Matrix Metalloproteinase 1
(metabolism)
- Matrix Metalloproteinase 13
- Mice
- Mitogen-Activated Protein Kinase 9
- Mitogen-Activated Protein Kinases
(metabolism)
- Mouth Neoplasms
(enzymology)
- Phenotype
- Phosphorylation
- Proto-Oncogene Proteins c-fos
(metabolism)
- Proto-Oncogene Proteins c-jun
(metabolism)
- RNA
(metabolism)
- Recombinant Proteins
(metabolism)
- Time Factors
- Transcription Factors
(metabolism)
- Transcription, Genetic
- Transfection
- Tumor Cells, Cultured
- p38 Mitogen-Activated Protein Kinases
|