MiR-422a promotes loco-regional recurrence by targeting NT5E/CD73 in head and neck squamous cell carcinoma
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Nathalie Bonnin1,2,3, Emma Armandy2,3, Julien Carras1,2, Sylvain Ferrandon2,3, Priscillia Battiston-Montagne2,3, Marc Aubry4,5,6, Sébastien Guihard7, David Meyronet1,3,8, Jean-Philippe Foy9, Pierre Saintigny9, Sonia Ledrappier7, Alain Jung7, Ruth Rimokh10, Claire Rodriguez-Lafrasse2,3,11, Delphine Poncet2,3,10,11
1Hospices Civils de Lyon, Lyon, France
2EMR3738, Equipe de Radiobiologie Cellulaire et Moléculaire, Faculté de Médecine Lyon Sud - Charles Mérieux, Oullins, France
3Université de Lyon, Lyon, France
4Université Rennes 1, Université Européenne de Bretagne, Biosit, Faculté de Médecine, Rennes, France
5Plate-forme Génomique Environnementale & Humaine Biogenouest, Biosit/OSUR, Rennes, France
6CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Rennes, France
7Laboratory for Tumor Biology and Tumor Bank Paul Strauss Cancer Center, EA3430 of The University of Strasbourg, Strasbourg, France
8“Stem Cell Transcriptomic Diversity” Team, Cancer Research Center of Lyon (CRCL), INSERM 1052-CNRS 5286, Lyon, France
9Department of Translational Research and Innovation, CRCL, INSERM 1052-CNRS 5286, Lyon, France
10“Signalization Metabolism and Tumor Progression” Team, CRCL, INSERM 1052-CNRS 5286, Lyon, France
11Biochemistry Department, Transfer and Molecular Oncology Unit, South Lyon Hospital, Hospices Civils de Lyon, Pierre Bénite, Lyon, France
Delphine Poncet, email: firstname.lastname@example.org
Keywords: HNSCC, CD73, miR-422a, personalized medicine
Received: February 26, 2016 Accepted: April 10, 2016 Published: June 04, 2016
At the time of diagnosis, 60% of patients with head and neck squamous cell carcinoma (HNSCC) present tumors in an advanced stage (III-IV) of disease and 80% will relapse within the first two years post-treatment, due to their frequent radio(chemo)resistance. To identify new molecular targets and companion biomarkers, we have investigated the miRNome of 75 stage III-IV oropharynx tumors without relapse (R) or with loco-regional relapse (non-responder, NR) within two years post-treatment. Interestingly, miR-422a was significantly downregulated in NR tumors, in agreement with the increase in cell proliferation and adhesion induced by miR-422a inhibition in vitro. Furthermore, we identified CD73/NT5E oncogene as target of miR-422a. Indeed, modulation of the endogenous level of miR-422a inversely influences the expression and the enzymatic activity of CD73. Moreover, knocking down CD73 mimics the effects of miR-422a upregulation. Importantly, in tumors, miR-422a and CD73 expression levels are inversely correlated, and both are predictive of relapse free survival - especially considering loco(regional) recurrence - in vitro two independent cohorts of advanced oropharynx or HNSCC (N=255) tumors. In all, we reported, for the first time, that MiR-422a and its target CD73 are involved in early loco(regional) recurrence of HNSCC tumors and are new targets for personalized medicine.
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