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Biglycan-mediated upregulation of MHC class I expression in HER-2/neu-transformed cells.

ABSTRACT: The extracellular matrix protein biglycan (BGN) has oncogenic or tumor suppressive potential depending on the cellular origin. HER-2/neu overexpression in murine fibroblasts and human model systems is inversely correlated with BGN expression. Upon its restoration BGNhigh HER-2/neu+ fibroblasts were less tumorigenic in immune competent mice when compared to BGNlow/neg HER-2/neu+ cells, which was associated with enhanced immune cell responses and higher frequencies of immune effector cells in tumors and peripheral blood. The increased immunogenicity of BGNhigh HER-2/neu+ fibroblasts appears to be due to upregulated MHC class I surface antigens and reduced expression levels of transforming growth factor (TGF)-? isoforms and the TGF-? receptor 1 suggesting a link between BGN, TGF-? pathway and HER-2/neu-mediated downregulation of MHC class I antigens. Treatment of BGNlow/neg HER-2/neu+ cells with recombinant BGN or an inhibitor of TGF-? enhanced MHC class I surface antigens in BGNlow/neg HER-2/neu-overexpressing murine fibroblasts, which was mediated by a transcriptional upregulation of major MHC class I antigen processing components. Furthermore, BGN expression in HER-2/neu+ cells was accompanied by an increased expression of the proteoglycan decorin (DCN). Since recombinant DCN also elevated MHC class I surface expression in BGNlow/neg HER-2/neu+ cells, both proteoglycans might act synergistically. This was in accordance with in silico analyses of mRNA data obtained from The Cancer Genome Atlas (TCGA) dataset available for breast cancer (BC) patients. Thus, our data provide for the first time evidence that proteoglycan signatures are modulated by HER-2/neu and linked to MHC class I-mediated immune escape associated with an altered TGF-? pathway.

SUBMITTER: Subbarayan K

PROVIDER: S-EPMC5889282 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Biglycan-mediated upregulation of MHC class I expression in HER-2/neu-transformed cells.

Subbarayan Karthikeyan K Leisz Sandra S Wickenhauser Claudia C Bethmann Daniel D Massa Chiara C Steven André A Seliger Barbara B

Oncoimmunology 20180116 4

The extracellular matrix protein biglycan (BGN) has oncogenic or tumor suppressive potential depending on the cellular origin. HER-2/neu overexpression in murine fibroblasts and human model systems is inversely correlated with BGN expression. Upon its restoration BGNhigh HER-2/neu+ fibroblasts were less tumorigenic in immune competent mice when compared to BGNlow/neg HER-2/neu+ cells, which was associated with enhanced immune cell responses and higher ...[more]

PMID: 29632715

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Project description:Chronic active antibody-mediated rejection is a major cause of allograft failure in kidney transplantation. Microvascular inflammation and transplant glomerulopathy are defining pathologic features of chronic active antibody-mediated rejection and are associated with allograft failure. However, the mechanisms of leukocyte infiltration and glomerular endothelial cell injury remain unclear. We hypothesized MHC class II ligation on glomerular endothelial cells (GEnC) would result in upregulation of adhesion molecules and production of chemoattractants. A model of endothelial cell activation in the presence of antibodies to MHC classes I and II was used to determine the expression of adhesion molecules and chemokines. Murine GEnC were activated with IFN?, which upregulated gene expression of ?2-microglobulin (MHC class I), ICAM1, VCAM1, CCL2, CCL5, and IL-6. IFN? stimulation of GEnC increased surface expression of MHC class I, MHC class II, ICAM1, and VCAM1. Incubation with antibodies directed at MHC class I or class II did not further enhance adhesion molecule expression. Multispectral imaging flow cytometry and confocal microscopy demonstrated MHC molecules co-localized with the adhesion molecules ICAM1 and VCAM1 on the GEnC surface. GEnC secretion of chemoattractants, CCL2 and CCL5, was increased by IFN? stimulation. CCL2 production was further enhanced by incubation with sensitized plasma. Endothelial activation induces de novo expression of MHC class II molecules and increases surface expression of MHC class I, ICAM1 and VCAM1, which are all co-localized together. Maintaining the integrity and functionality of the glomerular endothelium is necessary to ensure survival of the allograft. IFN? stimulation of GEnC propagates an inflammatory response with production of chemokines and co-localization of MHC and adhesion molecules on the GEnC surface, contributing to endothelial cell function as antigen presenting cells and an active player in allograft injury.

Dataset Information

Biglycan-mediated upregulation of MHC class I expression in HER-2/neu-transformed cells.

Publications

Biglycan-mediated upregulation of MHC class I expression in HER-2/neu-transformed cells.

Similar Datasets

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