Extravillous trophoblast-associated ADAM12 exerts pro-invasive properties, including induction of integrin beta 1-mediated cellular spreading.
ADAM12, consisting of a membrane-bound (ADAM12L) and a secreted (ADAM12S) form, is expressed exclusively in regenerating and developing tissue as well as in certain cancer types. Strong ADAM12 expression levels have been noticed in the human placenta, and deregulated ADAM12S levels were associated with various pregnancy-related disorders including pre-eclampsia and intrauterine growth restriction. However, the role of ADAM12 in trophoblast motility has not been investigated so far. Hence, the present study aimed to investigate the specific function of the protease by using different primary trophoblast cell models. Immunofluorescence and Western blot analyses of first trimester placental tissue and differentiating primary first trimester cytotrophoblasts (CTBs) indicated strong upregulation of both of the ADAM12 isoforms during extravillous trophoblast differentiation. Functional assays involving short interfering RNA (siRNA)-mediated knockdown studies in primary CTBs and first trimester explant cultures revealed a significant repression of trophoblast motility upon partial loss of ADAM12. Conversely, isoform-specific overexpression in the ADAM12-negative trophoblast cell line SGHPL-5 enhanced the invasive capacity of these cells. We further confirmed proteolytic activity of trophoblast-derived ADAM12S by demonstrating its potential to degrade insulin-like growth factor-binding protein 3. Finally, we suggest that ADAM12S exerts its pro-migratory function in trophoblasts by inducing integrin beta 1-mediated cellular spreading.
Department of Obstetrics and Fetal-Maternal Medicine, Reproductive Biology Unit, Medical University of Vienna, Austria.
Katarzyna
K
Biadasiewicz
Department of Obstetrics and Fetal-Maternal Medicine, Reproductive Biology Unit, Medical University of Vienna, Austria.
Valerie
V
Fock
Clinical Institute of Pathology, Medical University of Vienna, Austria.
Sabine
S
Dekan
Department of Obstetrics and Gynecology, Medical University of Vienna, Austria.
Katharina
K
Proestling
Department of Obstetrics and Fetal-Maternal Medicine, Reproductive Biology Unit, Medical University of Vienna, Austria.
Philipp
P
Velicky
Department of Obstetrics and Fetal-Maternal Medicine, Reproductive Biology Unit, Medical University of Vienna, Austria.
Sandra
S
Haider
Department of Obstetrics and Fetal-Maternal Medicine, Reproductive Biology Unit, Medical University of Vienna, Austria.
Martin
M
Knöfler
Department of Biomedical Sciences and Biotech Research & Innovation Centre, University of Copenhagen, Denmark.
Camilla
C
Fröhlich
Department of Obstetrics and Fetal-Maternal Medicine, Reproductive Biology Unit, Medical University of Vienna, Austria juergen.pollheimer@meduniwien.ac.at.
Jürgen
J
Pollheimer
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072199:ADAM12 Protein; D048868:Adaptor Proteins, Signal Transducing; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011261:Pregnancy Trimester, First / Q000378:metabolism; D020033:Protein Isoforms; D012313:RNA / Q000737:chemistry / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D014327:Trophoblasts / Q000378:metabolism*; D015854:Up-Regulation
D048868:Adaptor Proteins, Signal Transducing; C515497:IGFBP3 protein, human; C108257:ITGB1BP1 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D012313:RNA; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human
ADAM12; EVT; IGFBP3; ITGB1; molecular biology; motility; placenta; placentation; pregnancy; trophoblast