<i>MiR-422a</i> promotes loco-regional recurrence by targeting NT5E/CD73 in head and neck squamous cell carcinoma

Abstract

// Nathalie Bonnin 1, 2, 3 , Emma Armandy 2, 3 , Julien Carras 1, 2 , Sylvain Ferrandon 2, 3 , Priscillia Battiston-Montagne 2, 3 , Marc Aubry 4, 5, 6 , S&eacute;bastien Guihard 7 , David Meyronet 1, 3, 8 , Jean-Philippe Foy 9 , Pierre Saintigny 9 , Sonia Ledrappier 7 , Alain Jung 7 , Ruth Rimokh 10 , Claire Rodriguez-Lafrasse 2, 3, 11 , Delphine Poncet 2, 3, 10, 11 1 Hospices Civils de Lyon, Lyon, France 2 EMR3738, Equipe de Radiobiologie Cellulaire et Mol&eacute;culaire, Facult&eacute; de M&eacute;decine Lyon Sud - Charles M&eacute;rieux, Oullins, France 3 Universit&eacute; de Lyon, Lyon, France 4 Universit&eacute; Rennes 1, Universit&eacute; Europ&eacute;enne de Bretagne, Biosit, Facult&eacute; de M&eacute;decine, Rennes, France 5 Plate-forme G&eacute;nomique Environnementale &amp; Humaine Biogenouest, Biosit/OSUR, Rennes, France 6 CNRS, UMR 6290, Institut G&eacute;n&eacute;tique et D&eacute;veloppement de Rennes, Rennes, France 7 Laboratory for Tumor Biology and Tumor Bank Paul Strauss Cancer Center, EA3430 of The University of Strasbourg, Strasbourg, France 8 &ldquo;Stem Cell Transcriptomic Diversity&rdquo; Team, Cancer Research Center of Lyon (CRCL), INSERM 1052-CNRS 5286, Lyon, France 9 Department of Translational Research and Innovation, CRCL, INSERM 1052-CNRS 5286, Lyon, France 10 &ldquo;Signalization Metabolism and Tumor Progression&rdquo; Team, CRCL, INSERM 1052-CNRS 5286, Lyon, France 11 Biochemistry Department, Transfer and Molecular Oncology Unit, South Lyon Hospital, Hospices Civils de Lyon, Pierre B&eacute;nite, Lyon, France Correspondence to: Delphine Poncet, email: delphine.poncet@univ-lyon1.fr Keywords: HNSCC, CD73, miR-422a, personalized medicine Received: February 26, 2016&emsp;&emsp;&emsp;&emsp; Accepted: April 10, 2016&emsp;&emsp;&emsp;&emsp; Published: June 04, 2016 ABSTRACT 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.