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Progesterone-induced blocking factor differentially regulates trophoblast and tumor invasion by altering matrix metalloproteinase activity

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Abstract

Invasiveness is a common feature of trophoblast and tumors; however, while tumor invasion is uncontrolled, trophoblast invasion is strictly regulated. Both trophoblast and tumor cells express high levels of the immunomodulatory progesterone-induced blocking factor (PIBF), therefore, we aimed to test the possibility that PIBF might be involved in invasion. To this aim, we used PIBF-silenced or PIBF-treated trophoblast (HTR8/Svneo, and primary trophoblast) and tumor (HT-1080, A549, HCT116, PC3) cell lines. Silencing of PIBF increased invasiveness as well as MMP-2,-9 secretion of HTR8/SVneo, and decreased those of HT-1080 cells. PIBF induced immediate STAT6 activation in both cell lines. Silencing of IL-4Rα abrogated all the above effects of PIBF, suggesting that invasion-related signaling by PIBF is initiated through the IL-4Rα/PIBF-receptor complex. In HTR-8/SVneo, PIBF induced fast, but transient Akt and ERK phosphorylation, whereas in tumor cells, PIBF triggered sustained Akt, ERK, and late STAT3 activation. The late signaling events might be due to indirect action of PIBF. PIBF induced the expression of EGF and HB-EGF in HT-1080 cells. The STAT3-activating effect of PIBF was reduced in HB-EGF-deficient HT-1080 cells, suggesting that PIBF-induced HB-EGF contributes to late STAT3 activation. PIBF binds to the promoters of IL-6, EGF, and HB-EGF; however, the protein profile of the protein/DNA complex is different in the two cell lines. We conclude that in tumor cells, PIBF induces proteins, which activate invasion signaling, while—based on our previous data—PIBF might control trophoblast invasion by suppressing proinvasive genes.

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Abbreviations

BME:

Basement membrane extract

ECM:

Extracellular matrix

EGF:

Epidermal growth factor

EGFP:

Enhanced green fluorescent protein

Erk:

Extracellular signal-regulated protein kinase

Fli1:

Friend leukemia integration 1

GPI:

Glycophosphatidylinositol

HB-EGF:

Heparin-binding EGF-like growth factor

JAK:

Janus kinase

IL:

Interleukin

IL-4Rα:

Interleukin-4 receptor alpha

MAPK:

Mitogen-activated protein kinase

MMP:

Matrix metalloproteinase

NK:

Natural killer

PI-3K:

Phosphoinositide-3-kinase

PIBF:

Progesterone-induced blocking factor

PIBFR:

PIBF-receptor

PKC:

Protein kinase C

PlGF:

Placental growth factor

sHB-EGF:

soluble HB-EGF

STAT:

Signal transducer and activator of transcription

SV40:

Simian vacuolating virus 40

Tg:

Transgene

Th:

T helper

TIMP:

Tissue inhibitor of metalloproteinase

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Acknowledgments

We thank Dr. Charles Graham (Department of Anatomy and Cell Biology, Queen’s University, Kingston, Ontario, Canada L7L 3N6) for the gift of HTR8/SVneo cell line. We also thank Dr. Istvan Magyary (Faculty of Animal Science, Kaposvar University, Kaposvar, Hungary) for the zebrafish strain. This work was supported by the Hungarian National Research Fund (OTKA 77717), the University of Pécs (34039/KA-PostDoc12-03), the Hungarian Ministry of Health (ETT 286/2009), and the Research Team on Innovation (SROP-4.2.2/08/1/2008-0011), TÁMOP-4.2.1/B-10/1-2010-0002, and by TÁMOP-4.2.2.A-11/1/KONV-2012-0053.

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  1. Melinda Halasz

    Present address: Systems Biology Ireland Institute, University College Dublin, Dublin 4, Ireland

Authors and Affiliations

  1. Department of Medical Microbiology and Immunology, Medical School, University of Pécs, 12 Szigeti Street, Pécs, 7624, Hungary

    Melinda Halasz, Beata Polgar & Julia Szekeres-Bartho

  2. Department of Medical Biology, Medical School, University of Pécs, Pécs, 7624, Hungary

    Gergely Berta

  3. Department of Biophysics, Medical School, University of Pécs, Pécs, 7624, Hungary

    Livia Czimbalek

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  1. Melinda Halasz
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Correspondence to Julia Szekeres-Bartho.

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Halasz, M., Polgar, B., Berta, G. et al. Progesterone-induced blocking factor differentially regulates trophoblast and tumor invasion by altering matrix metalloproteinase activity. Cell. Mol. Life Sci. 70, 4617–4630 (2013). https://doi.org/10.1007/s00018-013-1404-3

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