Soluble HSPB1 regulates VEGF-mediated angiogenesis through their direct interaction

Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
Angiogenesis (Impact Factor: 4.88). 02/2012; 15(2):229-42. DOI: 10.1007/s10456-012-9255-3
Source: PubMed

ABSTRACT Endothelial cell function is critical for angiogenic balance in both physiological and pathological conditions, such as wound healing and cancer, respectively. We report here that soluble heat shock protein beta-1 (HSPB1) is released primarily from endothelial cells (ECs), and plays a key role in regulating angiogenic balance via direct interaction with vascular endothelial growth factor (VEGF). VEGF-mediated phosphorylation of intracellular HSPB1 inhibited the secretion of HSPB1 and their binding activity in ECs. Interestingly, co-culture of tumor ECs with tumor cells decreased HSPB1 secretion from tumor ECs, suggesting that inhibition of HSPB1 secretion allows VEGF to promote angiogenesis. Additionally, neutralization of HSPB1 in a primary mouse sarcoma model promoted tumor growth, indicating the anti-angiogenic role of soluble HSPB1. Overexpression of HSPB1 by HSPB1 adenovirus was sufficient to suppress lung metastases of CT26 colon carcinoma in vivo, while neutralization of HSPB1 promoted in vivo wound healing. While VEGF-induced regulation of angiogenesis has been studied extensively, these findings illustrate the key contribution of HSPB1-VEGF interactions in the balance between physiological and pathological angiogenesis.

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    • "HSPB1 is elevated in the serum of patients with many types of cancer, although its exact role in tumorigenesis and metastasis has yet to be determined [24], [25], [26]. Recently, we reported that soluble HSPB1 is released primarily from endothelial cells (ECs) [11]. To investigate the effect of soluble HSPB1 on tumor progression, we performed tumor cell transendothelial migration assays. "
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    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.
    PLoS ONE 01/2014; 9(1):e85509. DOI:10.1371/journal.pone.0085509 · 3.23 Impact Factor
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    • "A number of factors, including vascular endothelial growth factor-C (VEGF-C) and VEGF-D, hepatocyte growth factor, angiopoietin-1, platelet derived growth factor-BB, insulin-like growth factors 1 and 2, fibroblast growth factor-2, chronic inflammation, podoplanin, and macrophages, have been reported to promote endothelial cell proliferation, angiogenesis, migration, and survival via a number of pathways 13-37. These pathways include the VEGF-A/VEGFR-2, extracellular signal-regulated kinase 1/2, phosphatidylinositol 3-kinase/AKT, and the c-Jun NH2-terminal kinase ½ pathways 13-37. "
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    International journal of biological sciences 10/2012; 8(8):1206-16. DOI:10.7150/ijbs.5147 · 4.51 Impact Factor
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    ABSTRACT: Calcification of aortic valves results in valvular aortic stenosis and is becoming a common valvular condition in elderly populations. An understanding of the molecular mechanisms of this valve lesion is important for revealing potential biomarkers associated with the development and progression of this disease. In order to identify proteins that are differentially expressed in calcific aortic valves (CAVs) compared with those in adjacent normal valvular tissues, comprehensive analysis of differentially expressed proteins in the tissues was done by a quantitative proteomic approach with isobaric tag for absolute and relative quantitation labeling followed by nanoliquid chromatography matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry. The proteomic analysis revealed 105 proteins differentially expressed in CAVs in contrast to adjacent normal valvular tissues with high confidence. Significantly increased expression (>_1.3-fold) was found in 34 proteins, whereas decreased expression (<0.77-fold) was found in 39 proteins in CAVs. Among them, α-2-HS-glycoprotein showed the greatest increase in expression (6.54-fold) and tenascin-X showed the greatest decrease in expression (0.37-fold). Numerous extracellular matrix proteins such as collagens were identified as proteins with significantly decreased expression. Panther pathway analysis showed that some of the identified proteins were linked to blood coagulation and integrin signaling pathways. Cluster analysis of the 105 proteins differentially expressed in CAVs based on the expression pattern revealed that tenascin-X was clustered with proteins controlling collagen structure and function, especially collagen fibrillogenesis, such as decorin and fibromodulin. We confirmed decreased levels of these proteins in CAVs by Western blot analyses. These results indicated that massive destruction of the extracellular matrix occurs in CAVs.
    Connective tissue research 07/2012; 53(6). DOI:10.3109/03008207.2012.702818 · 1.61 Impact Factor
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