Abstract
In transitional cell carcinoma, the most common form of bladder cancer, overexpression of the matrix metalloproteinases MMP-2 and MMP-9 offers prognostic value as markers of disease-specific survival. These molecules have been implicated in metastasis of bladder cancer, but the underlying mechanisms through which they are controlled are poorly defined. In this study, we investigated a role of p38 mitogen-activated protein kinase (MAPK) in this process, using bladder cancer cell lines HTB9 and HTB5 that were derived from different tumor stages. p38 MAPK modulated MMP-2/9 mRNA levels at the levels of transcript stability and MMP-2/9 activity along with invasive capacity. We defined a downstream effector of p38 MAPK, MAPK-activated protein kinase 2 (MAPKAPK2), that was associated with MMP-2/9 activation. Ectopic expression of wild-type or constitutively active forms of MAPKAPK2 increased MMP-2/9 activities and invasive capacity. Conversely, p38 MAPK inhibition blocked the MAPKAPK2-mediated increase in MMP-2/9 activities and the invasive capacity of the cancer cells. Our findings implicate p38 MAPK and MAPKAPK2 in mediating bladder cancer invasion via regulation of MMP-2 and MMP-9 at the level of mRNA stability.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Growth Processes / physiology
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Cell Line, Tumor
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Cell Movement / physiology
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Humans
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Imidazoles / pharmacology
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Matrix Metalloproteinase 2 / biosynthesis
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Matrix Metalloproteinase 2 / genetics
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Matrix Metalloproteinase 2 / metabolism*
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Matrix Metalloproteinase 9 / biosynthesis
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / metabolism*
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Neoplasm Invasiveness
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Pyridines / pharmacology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Transfection
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Urinary Bladder Neoplasms / enzymology*
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Urinary Bladder Neoplasms / genetics
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Urinary Bladder Neoplasms / pathology
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
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Imidazoles
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Intracellular Signaling Peptides and Proteins
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Pyridines
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RNA, Messenger
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MAP-kinase-activated kinase 2
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Protein Serine-Threonine Kinases
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p38 Mitogen-Activated Protein Kinases
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Matrix Metalloproteinase 2
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Matrix Metalloproteinase 9
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SB 203580