Opposing roles of STAT-1 and STAT-3 in regulating vascular endothelial growth factor expression in vascular smooth muscle cells

Albasanz‐Puig, Adaia; Murray, Jacqueline; Namekata, Mayumi; Wijelath, Errol S.

doi:10.1016/j.bbrc.2012.10.037

Cited by 25 publications

(21 citation statements)

References 45 publications

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“…7). A study by Abasanz-Puig and colleagues 55 showed that STAT1 has a negative effect on HIF-1a in the vascular smooth muscle cells, which seems opposite to our findings as well as in other published studies in cancer cells. 45 One potential explanation for the differential effect of STAT1 on HIF-1a expression; i.e.…”

Section: Discussioncontrasting

confidence: 99%

Loss of WAVE3 sensitizes triple-negative breast cancers to chemotherapeutics by inhibiting the STAT-HIF-1α-mediated angiogenesis

et al. 2014

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Chemoresistance allows for disease to recur and ultimately causes the death of most breast cancer patients. This scenario is particularly relevant in patients harboring triple-negative breast cancer (TNBC) tumors for which there are no effective FDA-approved drugs. However, a recent study determined that TNBCs can be segregated into 6 genetically distinct subtypes that do in fact exhibit differential rates of pathological complete response (pCR) to standard-of-care chemotherapies. Of these, the mesenchymal and mesenchymal stem-like subtypes of TNBCs exhibit the lowest rates of pCR when treated with standard-of-care chemotherapies. WAVE3 is an actin-cytoskeleton remodeling protein, and recent studies have highlighted a potential role for WAVE3 in promoting tumor progression and metastasis in TNBC. However, whether WAVE3 activity is involved in the development of chemoresistance in TNBCs remains unclear. Here we show that loss of WAVE3 expression resensitizes human TNBC cells to doxorubicin and docetaxel, as measured by increased apoptosis and cell death. We also show that WAVE3 knockdown in the chemotherapy-treated TNBC cells results in inhibition of STAT1 phosphorylation, as well as a significant decrease in expression levels of its downstream effector HIF-1a. Since HIF-1a is a major activator of VEGF-A production, and therefore a stimulator of tumor angiogenesis, loss of HIF-1a in the WAVE3-knockdown cells resulted in the inhibition the chemotherapy-mediated VEGF-A secretion and the downstream activation of angiogenesis, a phenomenon that often accompanies chemoresistance. Our data identify a critical role of WAVE3 in sensitizing TNBC to chemotherapy by inhibiting the STAT1!HIF-1a!VEGF-A signaling axis, and support the possibility that WAVE3 inhibition may be a promising target for TNBC cancer therapy.

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Section: Discussioncontrasting

confidence: 99%

Loss of WAVE3 sensitizes triple-negative breast cancers to chemotherapeutics by inhibiting the STAT-HIF-1α-mediated angiogenesis

et al. 2014

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“…had first reported IL-17 could trigger JAK/STAT pathways in human monocytic leukemia cell line37. In addition, previous study showed that STAT-3 promoted VEGF expression by a target gene, while STAT-1 negatively regulated VEGF expression in vascular smooth muscle cells38. To further address the role of IL-17 signaling in VEGF production, we confirmed that IL-17 increased STAT1, STAT3 and JAK2 expression and promoted their phosphorylation in a time-dependent manner.…”

Section: Discussionsupporting

confidence: 63%

“…In vascular smooth muscle cells, STAT1 and STAT3 plays opposing roles in regulating the expression of VEGF. STAT1 inhibits VEGF expression, while STAT3 could promote the expression of VEGF16. Moreover, in human retinal pigment epithelial cell, JAK/STAT signaling pathway influences VEGF as well, since the STAT1 pathway inhibitor downregulated the secretion of VEGF17.…”

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confidence: 99%

IL-17 induces reactive astrocytes and up-regulation of vascular endothelial growth factor (VEGF) through JAK/STAT signaling

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et al. 2017

Sci Rep

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Spinal cord injury is a grave neurological disability resulting in neuron degeneration and permanent paralysis. The inflammation triggered by the injury would promote the spinal cord lesion in turn. Activated astrocytes during inflammatory response could promote glial scar formation and contribute to the progression of the spinal cord injury. Interleukin 17 (IL-17) was upregulated in inflammatory responses to contusion or compression of the spinal cord. in this study, IL-17 could induce reactive astrocytes which was indicated by a well-known hallmark glial fibrillary acidic protein (GFAP) in vitro and in vivo. Moreover, we demonstrated that the upregulation of VEGF was induced by IL-17 human astrocytoma cells. In our further investigation, IL-17 induced the expression of VEGF in spinal cord injury by activating JAK/STAT signaling pathway both in vitro and in vivo. In addition, we also found that IL-17 significantly changed tissue preservation and residual urine volumes and blood-spinal cord-barrier integrity in vivo. This newly found IL-17-JAK/STAT-VEGF axis improves our understanding of the molecular mechanism of spinal cord injury during inflammatory response and provides another potential target of spinal cord injury.

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“…Thus, HDL simultaneously inhibits the basal and IFNγ-induced expression (often STAT1-dependent [36]) of M1 markers, such as iNOS, IL-6 and TNFα. Antagonism between the STAT1 and STAT3 pathways is well described, notably in cardiovascular diseases [37], but reciprocal regulation between STAT1 and STAT6 is an emerging field [38], and our results may be reflecting such a phenomenon mediated by HDL with regard to macrophage inflammatory state.…”

Section: Discussionmentioning

confidence: 59%

HDL Induces the Expression of the M2 Macrophage Markers Arginase 1 and Fizz-1 in a STAT6-Dependent Process

2013

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Our lab has previously shown in a mouse model that normalization of a low HDL level achieves atherosclerotic plaque regression. This included the shift from a pro (“M1”) to an anti-inflammatory (“M2”) phenotypic state of plaque macrophages. Whether HDL can directly cause this phenotypic change and, if so, what the signaling mechanism is, were explored in the present studies. Murine primary macrophages treated with HDL showed increased gene expression for the M2 markers Arginase-1 (Arg-1) and Fizz-1, which are classically induced by IL-4. HDL was able to potentiate the IL-4-induced changes in Arg-1, and tended to do the same for Fizz-1, while suppressing the expression of inflammatory genes in response to IFNγ. The effects of either IL-4 or HDL were suppressed when macrophages were from STAT6-/- mice, but inhibitor studies suggested differential utilization of JAK isoforms by IL-4 and HDL to activate STAT6 by phosphorylation. Overall, our results describe a new function of HDL, namely its ability to directly enrich macrophages in markers of the M2, anti-inflammatory, state in a process requiring STAT6.

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Opposing roles of STAT-1 and STAT-3 in regulating vascular endothelial growth factor expression in vascular smooth muscle cells

Cited by 25 publications

References 45 publications

Loss of WAVE3 sensitizes triple-negative breast cancers to chemotherapeutics by inhibiting the STAT-HIF-1α-mediated angiogenesis

Loss of WAVE3 sensitizes triple-negative breast cancers to chemotherapeutics by inhibiting the STAT-HIF-1α-mediated angiogenesis

IL-17 induces reactive astrocytes and up-regulation of vascular endothelial growth factor (VEGF) through JAK/STAT signaling

HDL Induces the Expression of the M2 Macrophage Markers Arginase 1 and Fizz-1 in a STAT6-Dependent Process

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