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Epigenetic regulation of matrix metalloproteinases and their collagen substrates in cancer.

ABSTRACT: Our review covers the recent epigenetic data that are focused on matrix metalloproteinases (MMPs), their inhibitors (tissue inhibitors of MMPs; TIMPs) and collagen substrates. Twenty-four MMPs, four TIMPs and at least 28 collagen types are known in humans. The MMP activity regulates the functionality of multiple extracellular matrix proteins, cytokines, growth factors and cell signaling and adhesion receptors. Aberrantly enhanced MMP proteolysis affects multiple cell functions, including proliferation, migration and invasion. This aberrant MMP proteolysis is frequently recorded in cancer. Recent evidence, however, indicates that several MMPs function as tumor suppressors in cancer. Their inhibition could have pro-tumorigenic effects (making them anti-targets), counterbalancing the benefits of target inhibition and leading to adverse effects in cancer patients. The current epigenetic data suggest that there are distinct multi-layered epigenetic mechanisms that regulate MMPs, TIMPs and collagens. We show that in certain cancer types, epigenetic signatures of selected MMPs exhibit stem cell-like characteristics. Epigenetic mechanisms appear to play an especially important role in glioblastoma multiforme. Glioblastomas/gliomas synthesize de novo and then deposit collagens into the brain parenchyma. The collagen deposition, combined with an enhanced MMP activity in glioblastomas/gliomas, facilitates rapid invasion of tumor cells through the brain. It is tempting to hypothesize that the epigenetic mechanisms which control MMPs, TIMPs and collagens and, consequently, tumor cell invasion, represent promising drug targets and that in the near future these targets will be challenged pharmacologically.

SUBMITTER: Chernov AV

PROVIDER: S-EPMC3138141 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Epigenetic regulation of matrix metalloproteinases and their collagen substrates in cancer.

Chernov Andrei V AV Strongin Alex Y AY

Biomolecular concepts 20110601 3

Our review covers the recent epigenetic data that are focused on matrix metalloproteinases (MMPs), their inhibitors (tissue inhibitors of MMPs; TIMPs) and collagen substrates. Twenty-four MMPs, four TIMPs and at least 28 collagen types are known in humans. The MMP activity regulates the functionality of multiple extracellular matrix proteins, cytokines, growth factors and cell signaling and adhesion receptors. Aberrantly enhanced MMP proteolysis affects multiple cell functions, including prolife ...[more]

PMID: 21779312

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Project description:BACKGROUND:Chronic alcohol consumption has been shown in human and animal studies to result in collagen accumulation, myocardial fibrosis, and heart failure. Cardiac fibroblasts produce collagen and regulate extracellular matrix (ECM) homeostasis through the synthesis and activity of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs), with the balance of MMPs/TIMPs determining the rate of collagen turnover. Dynamic changes of MMP and TIMP expression were reported in alcohol-induced hepatic fibrosis; however, the effect of alcohol on MMP/TIMP balance in the heart and cardiac fibroblasts is unknown. We hypothesized that alcohol exposure alters cardiac fibroblast MMP and TIMP expression to promote collagen accumulation in the heart. METHODS:Cardiac fibroblasts isolated from adult rats were cultured in the presence of alcohol (12.5 to 200 mM) for 48 hours. MMP, TIMP, and collagen type I and III expression were assayed by Western blot analysis. Hydroxyproline (HPro) was used as a marker of collagen production. The in vivo cardiac effects of ethanol (EtOH) were determined using rats exposed to EtOH vapor for 2 weeks, resulting in blood alcohol levels of 150 to 200 mg/dl. Cardiac collagen volume fraction (CVF), as well as MMP, TIMP, and collagen expression, was assessed. RESULTS:EtOH-exposed rats exhibited up-regulation of TIMP-1, TIMP-3 and TIMP-4 in the heart, with no significant increases in MMPs. Cardiac fibroblasts exhibited transformation to a profibrotic phenotype following exposure to alcohol. These changes were reflected by increased ?-smooth muscle actin and collagen I and III expression, as well as increased collagen secretion. In vivo EtOH exposure also produced fibrosis, indicated by increased CVF and expression of collagens. CONCLUSIONS:Alcohol exposure modulates cardiac fibroblast MMP/TIMP expression favoring a profile associated with collagen accumulation. Our data suggest that this disrupted MMP/TIMP profile may contribute to the development of myocardial fibrosis and cardiac dysfunction resulting from chronic alcohol abuse.

Dataset Information

Epigenetic regulation of matrix metalloproteinases and their collagen substrates in cancer.

Publications

Epigenetic regulation of matrix metalloproteinases and their collagen substrates in cancer.

Similar Datasets

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