Progesterone-induced blocking factor differentially regulates trophoblast and tumor invasion by altering matrix metallop
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Cellular and Molecular Life Sciences
Research Article
Progesterone‑induced blocking factor differentially regulates trophoblast and tumor invasion by altering matrix metalloproteinase activity Melinda Halasz · Beata Polgar · Gergely Berta · Livia Czimbalek · Julia Szekeres‑Bartho
Received: 8 January 2013 / Revised: 9 June 2013 / Accepted: 10 June 2013 © Springer Basel 2013
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/PIBFreceptor 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 M. Halasz · B. Polgar · J. Szekeres‑Bartho (*) Department of Medical Microbiology and Immunology, Medical School, University of Pécs, 12 Szigeti Street, Pécs 7624, Hungary e-mail: [email protected] Present Address: M. Halasz Systems Biology Ireland Institute, University College Dublin, Dublin 4, Ireland G. Berta Department of Medical Biology, Medical School, University of Pécs, Pécs 7624, Hungary L. Czimbalek Department of Biophysics, Medical School, University of Pécs, Pécs 7624, Hungary
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. Keywords PIBF · Invasion · Tumor · Trophoblast · Zebrafish 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 Natura
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