Abstract
Matrix metalloproteinases regulate pathophysiological events by processing matrix proteins and secreted proteins. Previously, we demonstrated that soluble heat shock protein B1 (HSPB1) is released primarily from endothelial cells (ECs) and regulates angiogenesis via direct interaction with vascular endothelial growth factor (VEGF). Here we report that MMP9 can cleave HSPB1 and release anti-angiogenic fragments, which play a key role in tumorprogression. We mapped the cleavage sites and explored their physiological relevance during these processing events. HSPB1 cleavage by MMP9 inhibited VEGF-induced ECs activation and the C-terminal HSPB1 fragment exhibited more interaction with VEGF than did full-length HSPB1. HSPB1 cleavage occurs during B16F10 lung progression in wild-type mice. Also, intact HSPB1 was more detected on tumor endothelium of MMP9 null mice than wild type mice. Finally, we confirmed that secretion of C-terminal HSPB1 fragment was significantly inhibited lung and liver tumor progression of B16F10 melanoma cells and lung tumor progression of CT26 colon carcinoma cells, compared to full-length HSPB1. These data suggest that in vivo MMP9-mediated processing of HSPB1 acts to regulate VEGF-induced ECs activation for tumor progression, releasing anti-angiogenic HSPB1 fragments. Moreover, these findings potentially explain an anti-target effect for the failure of MMP inhibitors in clinical trials, suggesting that MMP inhibitors may have pro-tumorigenic effects by reducing HSPB1 fragmentation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Animals
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Carcinogenesis / genetics
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Carcinogenesis / metabolism
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Carcinogenesis / pathology*
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Cell Movement
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Cell Proliferation
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Disease Progression
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Endothelial Cells / metabolism
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HSP27 Heat-Shock Proteins / genetics
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HSP27 Heat-Shock Proteins / metabolism*
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Heat-Shock Proteins
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Humans
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / metabolism*
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Mice
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Molecular Chaperones
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Phosphorylation
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Receptors, Vascular Endothelial Growth Factor / genetics
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Receptors, Vascular Endothelial Growth Factor / metabolism*
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Sarcoma / genetics
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Sarcoma / metabolism
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Sarcoma / pathology
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Soft Tissue Neoplasms / genetics
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Soft Tissue Neoplasms / metabolism
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Soft Tissue Neoplasms / pathology
Substances
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HSP27 Heat-Shock Proteins
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HSPB1 protein, human
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Heat-Shock Proteins
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Molecular Chaperones
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Receptors, Vascular Endothelial Growth Factor
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Matrix Metalloproteinase 9
Grants and funding
This work was supported by the Nuclear Research and Development Program (Grant No. NRF-2012M2A2A7012483, NRF-2011-0031697 and NRF-2013M2A2A7043580) and a KIRAMS research project (Grant No. 50520-2013) funded by the Nuclear Research and Development Program. This work also supported by the Basic Science Research Program (Grant No. R1A4A002), Mid-career Researcher Program (Grant No. 2011-0013364) of the National Research Foundation of Korea (NRF), funded by the Korean Ministry of Education, Science, and Technology (MEST) and the Ewha Global Top5 Grant 2011 of Ewha Womans University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.