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Mol Biol Cell. 2013 Oct;24(20):3164-76. doi: 10.1091/mbc.E13-03-0142. Epub 2013 Aug 21.

Tissue-specific and SRSF1-dependent splicing of fibronectin, a matrix protein that controls host cell invasion.

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Institut de Génétique Moléculaire de Montpellier, CNRS UMR 5535/IFR122, Universities of Montpellier 1 and Montpellier 2, 34293 Montpellier Cedex 5, France Département de Physiologie, Université de Lausanne, CH-1015 Lausanne, Switzerland INSERM U844, Institut des Neurosciences de Montpellier, Centre Hospitalier Universitaire Saint Eloi, Université Montpellier 1, 34295 Montpellier Cedex 5, France Service Immuno-Rhumatologie, Centre Hospitalier Universitaire Lapeyronie, 34093 Montpellier Cedex, France.


Cell invasion targets specific tissues in physiological placental implantation and pathological metastasis, which raises questions about how this process is controlled. We compare dermis and endometrium capacities to support trophoblast invasion, using matching sets of human primary fibroblasts in a coculture assay with human placental explants. Substituting endometrium, the natural trophoblast target, with dermis dramatically reduces trophoblast interstitial invasion. Our data reveal that endometrium expresses a higher rate of the fibronectin (FN) extra type III domain A+ (EDA+) splicing isoform, which displays stronger matrix incorporation capacity. We demonstrate that the high FN content of the endometrium matrix, and not specifically the EDA domain, supports trophoblast invasion by showing that forced incorporation of plasma FN (EDA-) promotes efficient trophoblast invasion. We further show that the serine/arginine-rich protein serine/arginine-rich splicing factor 1 (SRSF1) is more highly expressed in endometrium and, using RNA interference, that it is involved in the higher EDA exon inclusion rate in endometrium. Our data therefore show a mechanism by which tissues can be distinguished, for their capacity to support invasion, by their different rates of EDA inclusion, linked to their SRSF1 protein levels. In the broader context of cancer pathology, the results suggest that SRSF1 might play a central role not only in the tumor cells, but also in the surrounding stroma.

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