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

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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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Basement membrane extract


Extracellular matrix


Epidermal growth factor


Enhanced green fluorescent protein


Extracellular signal-regulated protein kinase


Friend leukemia integration 1




Heparin-binding EGF-like growth factor


Janus kinase




Interleukin-4 receptor alpha


Mitogen-activated protein kinase


Matrix metalloproteinase


Natural killer




Progesterone-induced blocking factor




Protein kinase C


Placental growth factor


soluble HB-EGF


Signal transducer and activator of transcription


Simian vacuolating virus 40




T helper


Tissue inhibitor of metalloproteinase


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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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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).

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