Pharmacological inhibition of MIF interferes with trophoblast cell migration and invasiveness

Krivokuća, Milica Jovanović; Stefanoska, Ivana; Rabi, Tamara Abu; Al‐Abed, Yousef; Stošić-Grujičić, S.; Vićovac, Ljiljana

doi:10.1016/j.placenta.2014.12.003

Cited by 23 publications

(9 citation statements)

References 48 publications

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“…The MMP system is a well-documented effector mechanism important for trophoblast invasion 2,56 . Matrix metalloproteinases, MMP2 and MMP9, have been shown to mediate the influence of various cytokines and growth factors on trophoblast cell invasion 52,57,58 . MMP9 is able to degrade type IV collagen of the basement membrane, fibronectin, laminin, elastin, entactin, gelatin, and proteoglycans 59,60 .…”

Section: Discussionmentioning

confidence: 99%

“…MMP9 is able to degrade type IV collagen of the basement membrane, fibronectin, laminin, elastin, entactin, gelatin, and proteoglycans 59,60 . The regulation of MMPs is believed to occur at the transcriptional level, by activation of latent proenzymes, and by inhibition of proteolytic activity 58 . In this study, a decrease in MMP2 and MMP9 mRNA and reduced level/gelatinolytic activity of MMP2 and MMP9 in the conditioned media of galectin-3 silenced cells were observed, pointing to the significant contribution of post-transcriptional regulation of MMP expression.…”

Section: Discussionmentioning

confidence: 99%

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Human trophoblast requires galectin-3 for cell migration and invasion

Bojić‐Trbojević

Krivokuća

Vilotić

et al. 2019

Sci Rep

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Invasive extravillous cytotrophoblast of the human placenta expresses galectins-1, -3, and -8 in vivo and in vitro. This study aimed to investigate the potential role of galectin-3 in cell migration and invasion, using recombinant human galectin-3 (rhgalectin-3), small molecule galectin inhibitor I47, and galectin-3 silencing. HTR-8/SVneo cell migration was stimulated by rhgalectin-3 and reduced by I47, which could be neutralised by rhgalectin-3. Inhibitor specificity and selectivity for the galectins expressed in extravillous trophoblast were validated in solid phase assays using recombinant galectin-1, -3, -8, confirming selectivity for galectin-3. HTR-8/SVneo cell migration and invasion, and invasion by isolated trophoblast cells in primary culture were significantly reduced in the presence of I47, which could be restored by rhgalectin-3. Upon HTR-8/SVneo cell treatment with galectin-3 siRNA both LGALS3 and galectin-3 protein were dramatically decreased. Silencing of galectin-3 induced significant reduction in cell migration and invasion, which was restored by rhgalectin-3. The influence on known mediators of cell invasion, MMP2 and -9, and integrins α1, α5, and β1 was followed in silenced cells, showing lower levels of MMPs and a large reduction in integrin subunit β1. These results show that galectin-3 acts as a pro-invasive autocrine/paracrine factor in trophoblast in vitro.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Human trophoblast requires galectin-3 for cell migration and invasion

Bojić‐Trbojević

Krivokuća

Vilotić

et al. 2019

Sci Rep

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“…MIF is involved in a variety of physiological and pathological processes. In trophoblast, MIF was shown to support trophoblast invasion and migration in autocrine/paracrine manner [32]. Trophoblast and tumor cell invasion share multiple similarities including epithelial-mesenchymal transition (EMT) and degradation of extracellular matrix (ECM) by secreting proteolytic enzymes [33], the main difference being the fact that trophoblast invasion is under strict spatiotemporal control.…”

Section: Discussionmentioning

confidence: 99%

Macrophage migration inhibitory factor is differentially expressed in normal and choriocarcinoma trophoblast cells

Vilotić

Bojić‐Trbojević

Vićovac

et al. 2020

neo

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Trophoblast cells are specific for placenta, the organ necessary for development of the fetus. Trophoblast derived choriocarcinoma is a rare cancer, with high metastatic potential, invading surrounding tissues and distant organs. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine involved in a wide range of biological processes, which is increased in almost all human cancers. Expression of MIF in normal and choriocarcinoma trophoblast cells is investigated here, using normal extravillous trophoblast derived cell line HTR-8/SVneo, and choriocarcinoma cell lines JAR and JEG3. Expression of MIF and its receptors CD74 and CXCR2 was investigated at mRNA level using qPCR. Expression of MIF protein was studied using immunofluorescence and western blot, under reducing and native conditions, in whole cell lysates, subcellular fractions and conditioned media. The expression of MIF mRNA was similar in all three cell lines, while CD74 mRNA was more expressed in choriocarcinoma cells (14-fold for JAR, 12-fold for JEG3, p<0.01). CXCR2 mRNA was higher in JEG3 cell line compared to HTR-8/SVneo cells (6-fold, p<0.01). While the cellular level of MIF was similar, the level of secreted MIF was lower in JAR cell conditioned media compared to media of both HTR-8/SVneo (2.8-fold, p<0.01) and JEG3 cells (4.1-fold, p<0.001). Cellular distribution of MIF was similar between the studied cell types. MIF was predominantly cytoplasmic, but also detected in membrane, nuclear soluble and nuclear chromatin fraction. MIF appeared in high molecular weight complexes of >150 kDa under native conditions. A band of 140-145 kDa was consistently present in JEG3 cell lysates, while it was absent or very weak in other cell types. These results show that MIF/CD74 axis is shifted in choriocarcinoma, as previously shown for other cancers, and further justifies research towards the most effective MIF targeting therapeutics.

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“…Initially, we checked the cytotoxicity of rMIF, ISO-1, and T. gondii in HTR8/SVneo cells. The choice of dosages for the cytotoxicity assay was performed based on previous studies using different concentrations of rMIF (10–200 ng/ml) and ISO-1 (1–200 μg/ml) in HTR8/SVneo cells, which were not shown to be toxic to the cells (Krivokúca et al., 2014). Therefore, the experimental concentrations for the cytotoxicity assay in this study were 200 ng/ml for rMIF and 200 μg/ml for ISO-1 (diluted in DMSO).…”

Section: Discussionmentioning

confidence: 99%

“…Considering that MIF is important in the immune response against T. gondii , systemically and during gestation, and that the role of MIF in infected human extravillous trophoblast cells is unclear, the present study aimed to verify the functional role of MIF in HTR8/SVneo cells. HTR8/SVneo cells, a model of human extravillous trophoblast cells, are widely used to evaluate the migration and proliferation processes of extravillous trophoblast cells (Ko et al., 2013), to understand the factors involved during preeclampsia (Liu et al., 2018), and to examine the cellular effects of MIF in promoting cell migration and invasion (Krivokúca et al., 2014). For this reason, we verified the expression of the MIF receptor, intracellular proliferation of the parasite, and intracellular pathways triggered by MIF in HTR8/SVneo cells, using human recombinant MIF and ISO-1, a potent inhibitor of MIF activity according to the previous studies (Lubetsky et al., 2002; Liang et al., 2010; Sommerville et al., 2013; Krivokúca et al., 2014).…”

Section: Introductionmentioning

confidence: 99%

Increased Toxoplasma gondii Intracellular Proliferation in Human Extravillous Trophoblast Cells (HTR8/SVneo Line) Is Sequentially Triggered by MIF, ERK1/2, and COX-2

et al. 2019

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Macrophage migration inhibitory factor (MIF) is a potent pro-inflammatory cytokine, which mediates the regulation of diverse cellular functions. It is produced by extravillous trophoblastic cells and has been found to be involved in the pathogenesis of diseases caused by some protozoa, including Toxoplasma gondii . Previous studies demonstrated the ability of T. gondii to take advantage of MIF action in human trophoblast cells. However, MIF action in T. gondii -infected extravillous trophoblastic cells (HTR8/SVneo cell line) has not been fully investigated. The present study aimed to investigate the role of MIF in T. gondii -infected HTR8/SVneo cells and verify the intracellular signaling pathways triggered by this cytokine. We found that T. gondii increased MIF production by HTR8/SVneo cells, and by contrast, MIF inhibition, by ISO-1, led to a significant decrease in T. gondii proliferation and CD74 expression in HTR8/SVneo cells. Moreover, in infected HTR8/SVneo cells, the addition of recombinant MIF (rMIF) increased CD44 co-receptor expression, ERK1/2 phosphorylation, COX-2 expression, and IL-8 production, which favored T. gondii proliferation. Our findings indicate that T. gondii can use MIF to modulate important factors in HTR8/SVneo cells, being a possible explanation for the higher susceptibility of extravillous trophoblast cells than other trophoblast cell populations.

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Pharmacological inhibition of MIF interferes with trophoblast cell migration and invasiveness

Cited by 23 publications

References 48 publications

Human trophoblast requires galectin-3 for cell migration and invasion

Human trophoblast requires galectin-3 for cell migration and invasion

Macrophage migration inhibitory factor is differentially expressed in normal and choriocarcinoma trophoblast cells

Increased Toxoplasma gondii Intracellular Proliferation in Human Extravillous Trophoblast Cells (HTR8/SVneo Line) Is Sequentially Triggered by MIF, ERK1/2, and COX-2

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