hnRNP A1-mediated translational regulation of the G quadruplex-containing RON receptor tyrosine kinase mRNA linked to tumor progression
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Anne Cammas1,2,*, Magali Lacroix-Triki1,2,3,*, Sandra Pierredon1,2,3, Morgane Le Bras1,2, Jason S. Iacovoni1,2, Marie-Paule Teulade-Fichou4,5, Gilles Favre1,2,3, Henri Roché1,2,3, Thomas Filleron3, Stefania Millevoi1,2, Stéphan Vagner6,7,8
1INSERM UMR 1037, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
2Université Toulouse III Paul Sabatier, Toulouse, France
3Institut Claudius Regaud, Toulouse, France
4Institut Curie, PSL Research University, CNRS UMR 176, Orsay, France
5Institut Curie, PSL Research University, CNRS UMR 3348, Orsay, France
6Université Paris Sud, Université Paris-Saclay, CNRS UMR 176, Orsay, France
7Université Paris Sud, Université Paris-Saclay, CNRS UMR 3348, Orsay, France
8Equipe Labellisée Ligue Contre le Cancer, Paris, France
*These authors have contributed equally to this work
Stéphan Vagner, e-mail: firstname.lastname@example.org
Keywords: breast cancer, metastasis, RNA-binding protein, RON, translation
Received: July 21, 2015 Accepted: January 13, 2016 Published: February 22, 2016
The expression and role of RNA binding proteins (RBPs) controlling mRNA translation during tumor progression remains largely uncharacterized. Analysis by immunohistochemistry of the expression of hnRNP A1, hnRNPH, RBM9/FOX2, SRSF1/ASF/SF2, SRSF2/SC35, SRSF3/SRp20, SRSF7/9G8 in breast tumors shows that the expression of hnRNP A1, but not the other tested RBPs, is associated with metastatic relapse. Strikingly, hnRNP A1, a nuclear splicing regulator, is also present in the cytoplasm of tumor cells of a subset of patients displaying exceedingly worse prognosis. Expression of a cytoplasmic mutant of hnRNP A1 leads to increased translation of the mRNA encoding the tyrosine kinase receptor RON/MTS1R, known for its function in tumor dissemination, and increases cell migration in vitro. hnRNP A1 directly binds to the 5' untranslated region of the RON mRNA and activates its translation through G-quadruplex RNA secondary structures. The correlation between hnRNP A1 and RON tumoral expression suggests that these findings hold clinical relevance.
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