hnRNP A1-mediated translational regulation of the G quadruplex-containing RON receptor tyrosine kinase mRNA linked to tumor progression

// Anne Cammas 1, 2, * , Magali Lacroix-Triki 1, 2, 3, * , Sandra Pierredon 1, 2, 3 , Morgane Le Bras 1, 2 , Jason S. Iacovoni 1, 2 , Marie-Paule Teulade-Fichou 4, 5 , Gilles Favre 1, 2, 3 , Henri Roche 1, 2, 3 , Thomas Filleron 3 , Stefania Millevoi 1, 2 , Stephan Vagner 6, 7, 8 1 INSERM UMR 1037, Centre de Recherches en Cancerologie de Toulouse, Toulouse, France 2 Universite Toulouse III Paul Sabatier, Toulouse, France 3 Institut Claudius Regaud, Toulouse, France 4 Institut Curie, PSL Research University, CNRS UMR 176, Orsay, France 5 Institut Curie, PSL Research University, CNRS UMR 3348, Orsay, France 6 Universite Paris Sud, Universite Paris-Saclay, CNRS UMR 176, Orsay, France 7 Universite Paris Sud, Universite Paris-Saclay, CNRS UMR 3348, Orsay, France 8 Equipe Labellisee Ligue Contre le Cancer, Paris, France * These authors have contributed equally to this work Correspondence to: Stephan Vagner, e-mail: stephan.vagner@curie.fr Keywords: breast cancer, metastasis, RNA-binding protein, RON, translation Received: July 21, 2015     Accepted: January 13, 2016     Published: February 22, 2016 ABSTRACT 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.