Stanniocalcin-1 regulates endothelial gene expression and modulates transendothelial migration of leukocytes

Chakraborty, Arup; Brooks, Heddwen L.; Zhang, Ping; Smith, William E.; McReynolds, Matthew R.; Hoying, Jay B; Bick, Roger J.; Truong, Luan D.; Poindexter, Brian J.; Lan, Hui‐Yao; Elbjeirami, Wafa M.; Sheikh-Hamad, David

doi:10.1152/ajprenal.00219.2006

Cited by 55 publications

(54 citation statements)

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“…Furthermore, we have also shown STC1 to regulate the expression of many genes in human endothelial cells. 11 Collectively, these data indicate that STC1 plays a protective role in regulating endothelial cell functions.…”

Section: Discussionmentioning

confidence: 85%

“…These discoveries are complementary to recent observations suggesting that STC1 inhibits transendothelial migration of macrophages and T-lymphocytes through quiescent or IL-1␤-activated human umbilical vein endothelial cells (HUVECs) in vitro. 11 In addition, STC1 regulates gene expression in cultured endothelial cells, and is detected on the apical surface of endothelial cells in vivo. We previously showed increased expression of STC1 in cardiac vessels and cardiomyocytes of patients with dilated cardiomyopathy.…”

Section: Discussionmentioning

confidence: 99%

“…16 The expression of STC1 mRNA in endothelial cells and the remarkable increase in the expression of STC1 protein in blood vessels of the failing heart suggested an important role for this protein in the vascular system. Studies from our laboratories also suggest that STC1 suppresses inflammation 11,17 ; however, it is unknown whether STC1 plays a role in endothelial barrier function, particularly during inflammation. Because heart failure and atheresoclerosis are characterized by increased oxidative stress 18 and upregulated expression of inflammatory cytokines such as TNF-␣, IL-1, and IL-6, 19 we hypothesized that STC1 may inhibit cyctokineinduced endothelial permeability and thus may maintain endothelial integrity in the failing heart and atherosclerotic vessels.…”

mentioning

confidence: 93%

“…For example, STC1 inhibited chemotaxis of mouse macrophages and human monoblasts in response to monocyte chemotactic protein-1 (MCP-1) and stromal cell-derived factor-1 alpha (SDF1-␣) 10 and decreased transmigration of macrophages and T-lymphocytes across quiescent or interleukin (IL)-1 beta (IL-1␤)-activated human endothelial cells. 11 Despite the growing body of knowledge about STC1, little is known about its effects on the vascular system and how it might affect endothelial barrier function during inflammation.…”

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confidence: 99%

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Human Stanniocalcin-1 Blocks TNF-α–Induced Monolayer Permeability in Human Coronary Artery Endothelial Cells

Chen

Jamaluddin

Yan

et al. 2008

ATVB

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Objective-Our previous studies revealed upregulation of stanniocalcin-1 (STC1) in cardiac vessels in dilated cardiomyopathy. However, the functional significance of STC1 is unknown. The objective of this study was to determine the effects of STC1 on TNF-␣-induced monolayer permeability of human coronary artery endothelial cells (HCAECs). Methods and Results-Cells were pretreated with STC1 for 30 minutes followed by treatment with TNF-␣ (2 ng/mL) for 24 hours. Monolayer permeability was studied using a transwell system. STC1 pretreatment significantly blocked TNF-␣-induced monolayer permeability in a concentration-and time-dependent manner. STC1 effectively blocked TNF-␣-induced downregulation of endothelial tight junction proteins zonula occluden-1 and claudin-1 at both mRNA and protein levels. STC1 also significantly decreased TNF-␣-induced superoxide anion production. The inhibitory effect of STC1 was specific to TNF-␣, as it failed to inhibit VEGF-induced endothelial permeability. Key Words: stanniocalcin-1 Ⅲ TNF-␣ Ⅲ endothelial cell Ⅲ permeability Ⅲ superoxide anion S tanniocalcin 1 (STC1) is a 25-kDa disulfide-linked homodimeric glycoprotein, which was originally identified as a secretory hormone of the corpuscles of Stannius, an endocrine gland unique to bony fish. 1 The mammalian homolog of STC1 has been found in many species including humans, rats, and mice. 2,3 Human STC1 is encoded by a single copy gene located on chromosome 8p11.2-p21 and comprises 4 exons that encode 247 amino acids with 11 cysteine residues. 2,3 Human and mouse STC1 proteins have 98% amino acid identity and share 73% overall sequence homology to fish STC. 2 Unlike the localized expression of STC1 in fish, mammalian STC1 is not detected in the blood and is expressed in many organs including the kidney, intestine, heart, thyroid, lung, placenta, brain, and bone, 4,5 suggesting a paracrine rather than an endocrine role for STC1 in mammals. The primary function of STC in fish is to prevent hypercalcemia 6 by inhibiting calcium influx through the gills and gut and stimulating phosphate reabsorption by the kidneys. 7 Similarly, in rodents, STC1 reduces the intestinal uptake of calcium while enhancing that of phosphate. 8 Furthermore, this gene seems to play diverse roles in numerous developmental, physiological, and pathological processes including cancer, pregnancy, lactation, angiogenesis, organogenesis, cerebral ischemia, and hypertonic stress. 9 Studies also indicate that STC1 modulates inflammation. For example, STC1 inhibited chemotaxis of mouse macrophages and human monoblasts in response to monocyte chemotactic protein-1 (MCP-1) and stromal cell-derived factor-1 alpha (SDF1-␣) 10 and decreased transmigration of macrophages and T-lymphocytes across quiescent or interleukin (IL)-1 beta (IL-1␤)-activated human endothelial cells. 11 Despite the growing body of knowledge about STC1, little is known about its effects on the vascular system and how it might affect endothelial barrier function during inflammation.The endothelial barrier i...

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 93%

mentioning

confidence: 99%

See 2 more Smart Citations

Human Stanniocalcin-1 Blocks TNF-α–Induced Monolayer Permeability in Human Coronary Artery Endothelial Cells

Chen

Jamaluddin

Yan

et al. 2008

ATVB

Self Cite

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“…However, this issue should be revisited by expanded analyses of various subsets of additional tumor stromal cells, such as fibroblasts, pericytes, and neutrophils. These future analyses should also consider recent studies, which have implicated STC1, in noncancer models, as a regulator of inflammation, macrophage mobility, and vascular permeability (39)(40)(41)(42). Interestingly, earlier studies have also shown that hypoxia, a prometastatic stimuli, also leads to the upregulation of STC1 (43).…”

Section: Discussionmentioning

confidence: 88%

STC1 Expression By Cancer-Associated Fibroblasts Drives Metastasis of Colorectal Cancer

et al. 2013

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Platelet-derived growth factor (PDGF) receptor signaling is a major functional determinant of cancerassociated fibroblasts (CAF). Elevated expression of PDGF receptors on stromal CAFs is associated with metastasis and poor prognosis, but mechanism(s) that underlie these connections are not understood. Here, we report the identification of the secreted glycoprotein stanniocalcin-1 (STC1) as a mediator of metastasis by PDGF receptor function in the setting of colorectal cancer. PDGF-stimulated fibroblasts increased migration and invasion of cocultured colorectal cancer cells in an STC1-dependent manner. Analyses of human colorectal cancers revealed significant associations between stromal PDGF receptor and STC1 expression. In an orthotopic mouse model of colorectal cancer, tumors formed in the presence of STC1-deficient fibroblasts displayed reduced intravasation of tumor cells along with fewer and smaller distant metastases formed. Our results reveal a mechanistic basis for understanding the contribution of PDGF-activated CAFs to cancer metastasis. Cancer Res; 73(4);

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Multipotent stromal cells are activated to reduce apoptosis in part by upregulation and secretion of stanniocalcin-1

et al. 2009

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Multipotent stromal cells (MSCs) have been shown to reduce apoptosis in injured cells by secretion of paracrine factors, but these factors were not fully defined. We observed that co-culture of MSCs with previously UV irradiated fibroblasts reduced apoptosis of the irradiated cells, but fresh MSC conditioned media was unable reproduce the effect. Comparative Microarray analysis of MSCs grown in the presence or absence of UV irradiated fibroblasts demonstrated that the MSCs were activated by the apoptotic cells to increase synthesis and secretion of stanniocalcin-1 (STC-1), a peptide hormone that modulates mineral metabolism and has pleiotrophic effects that have not been fully characterized. We showed that STC-1 was required but not sufficient for reduction of apoptosis of UV-irradiated fibroblasts. In contrast, we demonstrated that MSC-derived STC-1 was both required and sufficient for reduction of apoptosis of lung cancer epithelial cells made apoptotic by incubation at low pH in hypoxia. Our data demonstrate that STC-1 mediates the anti-apoptotic effects of MSCs in two distinct models of apoptosis in vitro.

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Stanniocalcin-1 regulates endothelial gene expression and modulates transendothelial migration of leukocytes

Cited by 55 publications

References 50 publications

Human Stanniocalcin-1 Blocks TNF-α–Induced Monolayer Permeability in Human Coronary Artery Endothelial Cells

Human Stanniocalcin-1 Blocks TNF-α–Induced Monolayer Permeability in Human Coronary Artery Endothelial Cells

STC1 Expression By Cancer-Associated Fibroblasts Drives Metastasis of Colorectal Cancer

Multipotent stromal cells are activated to reduce apoptosis in part by upregulation and secretion of stanniocalcin-1

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