Lack of Fetuin-A (α2-HS-Glycoprotein) Reduces Mammary Tumor Incidence and Prolongs Tumor Latency via the Transforming Growth Factor-β Signaling Pathway in a Mouse Model of Breast Cancer

Guillory, Bobby; Sakwe, Amos M.; Saria, Margret; Thompson, Pamela; Adhiambo, Christine; Koumangoye, Rainelli; Ballard, Billy R.; Binhazim, Awadh A.; Cone, Cecil; Jahanen-Dechent, Willi; Ochieng, Josiah

doi:10.2353/ajpath.2010.100177

Cited by 40 publications

(55 citation statements)

References 40 publications

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“…The ability of fetuin-A to promote the rapid adhesion of cells to extracellular matrix proteins could explain why media containing fetal bovine serum, that contains a high concentration of the protein, is preferred for the culture of tumor cells [7,8]. Furthermore, in vivo studies support the tumor adhesion and growth promoting properties of fetuin-A [4,32]. …”

Section: Discussionmentioning

confidence: 99%

“…The widely accepted physiological function of this protein is the inhibition of ectopic calcification [1]. However, it also modulates a number of signaling pathways including those involving TGF-β and insulin [2,3,4,5]. Because of its widespread involvement in so many physiological mechanisms, fetuin-A is now considered a multi-functional protein [6].…”

Section: Introductionmentioning

confidence: 99%

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Fetuin-A associates with histones intracellularly and shuttles them to exosomes to promote focal adhesion assembly resulting in rapid adhesion and spreading in breast carcinoma cells

Nangami

Koumangoye

Goodwin

et al. 2014

Experimental Cell Research

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The present analyses were undertaken to define the mechanisms by which fetuin-A modulates cellular adhesion. FLAG-tagged fetuin-A was expressed in breast carcinoma and HEK-293T cells. We demonstrated by confocal microscopy that fetuin-A co-localizes with histone H2A in the cell nucleus, forms stable complexes with histones such as H2A and H3 in solution, and shuttles histones to exosomes. The rate of cellular adhesion and spreading to either fibronectin or laminin coated wells was accelerated significantly in the presence of either endogenous fetuin-A or serum derived protein. More importantly, the formation of focal adhesion complexes on surfaces coated by laminin or fibronectin was accelerated in the presence of fetuin-A or histone coated exosomes. Cellular adhesion mediated by histone coated exosomes was abrogated by heparin and heparinase III. Heparinase III cleaves heparan sulfate from cell surface heparan sulfate proteoglycans. Lastly, the uptake of histone coated exosomes and subsequent cellular adhesion, was abrogated by heparin. Taken together, the data suggest a mechanism where fetuin-A, either endogenously synthesized or supplied extracellularly can extract histones from the nucleus or elsewhere in the cytosol/membrane and load them on cellular exosomes which then mediate adhesion by interacting with cell surface heparan sulfate proteoglycans via bound histones.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fetuin-A associates with histones intracellularly and shuttles them to exosomes to promote focal adhesion assembly resulting in rapid adhesion and spreading in breast carcinoma cells

Nangami

Koumangoye

Goodwin

et al. 2014

Experimental Cell Research

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“…AHSG is associated with brain development and immune function including functioning as an anti-inflammatory mediator that participates in the inhibition of apoptosis of vascular smooth muscle cells [8]. It is a negative acute phase response protein [9], whose production decreases as disease load increases. We have shown, using in vivo animal models, that AHSG promotes breast cancer progression [9] and Lewis Lung Carcinoma tumorigenesis [10].…”

Section: Introductionmentioning

confidence: 99%

“…It is a negative acute phase response protein [9], whose production decreases as disease load increases. We have shown, using in vivo animal models, that AHSG promotes breast cancer progression [9] and Lewis Lung Carcinoma tumorigenesis [10]. AHSG has been shown to be TGF-β receptor mimic in that its TRHI (TGF-β receptor II homology domain I) motif closely resembles the TGF-β receptor II in structure.…”

Section: Introductionmentioning

confidence: 99%

Alpha-2 Heremans Schmid Glycoprotein (AHSG) Modulates Signaling Pathways in Head and Neck Squamous Cell Carcinoma Cell Line SQ20B

Thompson

Sakwe

Koumangoye

et al. 2014

Experimental Cell Research

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This study was performed to identify the potential role of Alpha-2 Heremans Schmid Glycoprotein (AHSG) in Head and Neck Squamous Cell Carcinoma (HNSCC) tumorigenesis using an HNSCC cell line model. HNSCC cell lines are unique among cancer cell lines, in that they produce endogenous AHSG and do not rely, solely, on AHSG derived from serum. To produce our model, we performed a stable transfection to down-regulate AHSG in the HNSCC cell line SQ20B, resulting in three SQ20B sublines, AH50 with 50% AHSG production, AH20 with 20% AHSG production and EV which is the empty vector control expressing wild-type levels of AHSG. Utilizing these sublines, we examined the effect of AHSG depletion on cellular adhesion, proliferation, migration and invasion in a serum-free environment. We demonstrated that sublines EV and AH50 adhered to plastic and laminin significantly faster than the AH20 cell line, supporting the previously reported role of exogenous AHSG in cell adhesion. As for proliferative potential, EV had the greatest amount of proliferation with AH50 proliferation significantly diminished. AH20 cells did not proliferate at all. Depletion of AHSG also diminished cellular migration and invasion. TGF-β was examined to determine whether levels of the TGF-β binding AHSG influenced the effect of TGF-β on cell signaling and proliferation. Whereas higher levels of AHSG blunted TGF-β influenced SMAD and ERK signaling, it did not clearly affect proliferation, suggesting that AHSG influences on adhesion, proliferation, invasion and migration are primarily due to its role in adhesion and cell spreading. The previously reported role of AHSG in potentiating metastasis via protecting MMP-9 from autolysis was also supported in this cell line based model system of endogenous AHSG production in HNSCC. Together, these data show that endogenously produced AHSG in an HNSCC cell line, promotes in vitro cellular properties identified as having a role in tumorigenesis.

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“…Along those lines, fetuin-A may contribute to type II diabetes [16]. Fetuin-A has further been shown to modify the inflammatory response [17,18,19] and to foster tumor growth [20]. …”

Section: Introductionmentioning

confidence: 99%

Up-Regulation of Hepatic Alpha-2-HS-Glycoprotein Transcription by TestosteroneviaAndrogen Receptor Activation

Voelkl

Pakladok

Lin

et al. 2014

Cell Physiol Biochem

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Background/Aims: Fetuin-A (alpha-2-HS-glycoprotein, AHSG), a liver borne plasma protein, contributes to the prevention of soft tissue calcification, modulates inflammation, reduces insulin sensitivity and fosters weight gain following high fat diet or ageing. In polycystic ovary syndrome, fetuin-A levels correlate with free androgen levels, an observation pointing to androgen sensitivity of fetuin-A expression. The present study thus explored whether the expression of hepatic fetuin-A is modified by testosterone. Methods: HepG2 cells were treated with testosterone and androgen receptor antagonist flutamide, and were silenced with androgen receptor siRNA. To test the in vivo relevance, male mice were subjected to androgen deprivation therapy (ADT) for 7 weeks. AHSG mRNA levels were determined by quantitative RT-PCR and fetuin-A protein abundance by Western blotting. Results: In HepG2 cells, AHSG mRNA expression and fetuin-A protein abundance were both up-regulated following testosterone treatment. The human alpha-2-HS-glycoprotein gene harbors putative androgen receptor response elements in the proximal 5 kb promoter sequence relative to TSS. The effect of testosterone on AHSG mRNA levels was abrogated by silencing of the androgen receptor in HepG2 cells. Moreover, treatment of HepG2 cells with the androgen receptor antagonist flutamide in presence of endogenous ligands in the medium significantly down-regulated AHSG mRNA expression and fetuin-A protein abundance. In addition, ADT of male mice was followed by a significant decrease of hepatic Ahsg mRNA expression and fetuin-A protein levels. Conclusions: Testosterone participates in the regulation of hepatic fetuin-A expression, an effect mediated, at least partially, by androgen receptor activation.

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Lack of Fetuin-A (α2-HS-Glycoprotein) Reduces Mammary Tumor Incidence and Prolongs Tumor Latency via the Transforming Growth Factor-β Signaling Pathway in a Mouse Model of Breast Cancer

Cited by 40 publications

References 40 publications

Fetuin-A associates with histones intracellularly and shuttles them to exosomes to promote focal adhesion assembly resulting in rapid adhesion and spreading in breast carcinoma cells

Fetuin-A associates with histones intracellularly and shuttles them to exosomes to promote focal adhesion assembly resulting in rapid adhesion and spreading in breast carcinoma cells

Alpha-2 Heremans Schmid Glycoprotein (AHSG) Modulates Signaling Pathways in Head and Neck Squamous Cell Carcinoma Cell Line SQ20B

Up-Regulation of Hepatic Alpha-2-HS-Glycoprotein Transcription by TestosteroneviaAndrogen Receptor Activation

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