MiR-422a promotes loco-regional recurrence by targeting NT5E/CD73 in head and neck squamous cell carcinoma.
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.
Hospices Civils de Lyon, Lyon, France.|EMR3738, Equipe de Radiobiologie Cellulaire et Moléculaire, Faculté de Médecine Lyon Sud - Charles Mérieux, Oullins, France.|Université de Lyon, Lyon, France.
Nathalie
N
Bonnin
EMR3738, Equipe de Radiobiologie Cellulaire et Moléculaire, Faculté de Médecine Lyon Sud - Charles Mérieux, Oullins, France.|Université de Lyon, Lyon, France.
Emma
E
Armandy
Hospices Civils de Lyon, Lyon, France.|EMR3738, Equipe de Radiobiologie Cellulaire et Moléculaire, Faculté de Médecine Lyon Sud - Charles Mérieux, Oullins, France.
Julien
J
Carras
EMR3738, Equipe de Radiobiologie Cellulaire et Moléculaire, Faculté de Médecine Lyon Sud - Charles Mérieux, Oullins, France.|Université de Lyon, Lyon, France.
Sylvain
S
Ferrandon
EMR3738, Equipe de Radiobiologie Cellulaire et Moléculaire, Faculté de Médecine Lyon Sud - Charles Mérieux, Oullins, France.|Université de Lyon, Lyon, France.
Priscillia
P
Battiston-Montagne
Université Rennes 1, Université Européenne de Bretagne, Biosit, Faculté de Médecine, Rennes, France.|Plate-forme Génomique Environnementale & Humaine Biogenouest, Biosit/OSUR, Rennes, France.|CNRS, UMR 6290, Institut Génétique et Développement de Rennes, Rennes, France.
Marc
M
Aubry
Laboratory for Tumor Biology and Tumor Bank Paul Strauss Cancer Center, EA3430 of The University of Strasbourg, Strasbourg, France.
Sébastien
S
Guihard
Hospices Civils de Lyon, Lyon, France.|Université de Lyon, Lyon, France.|“Stem Cell Transcriptomic Diversity” Team, Cancer Research Center of Lyon (CRCL), INSERM 1052-CNRS 5286,  Lyon, France.
David
D
Meyronet
Department of Translational Research and Innovation, CRCL, INSERM 1052-CNRS 5286, Lyon, France.
Jean-Philippe
JP
Foy
Department of Translational Research and Innovation, CRCL, INSERM 1052-CNRS 5286, Lyon, France.
Pierre
P
Saintigny
Laboratory for Tumor Biology and Tumor Bank Paul Strauss Cancer Center, EA3430 of The University of Strasbourg, Strasbourg, France.
Sonia
S
Ledrappier
Laboratory for Tumor Biology and Tumor Bank Paul Strauss Cancer Center, EA3430 of The University of Strasbourg, Strasbourg, France.
Alain
A
Jung
“Signalization Metabolism and Tumor Progression” Team, CRCL, INSERM 1052-CNRS 5286,  Lyon, France.
Ruth
R
Rimokh
EMR3738, Equipe de Radiobiologie Cellulaire et Moléculaire, Faculté de Médecine Lyon Sud - Charles Mérieux, Oullins, France.|Université de Lyon, Lyon, France.|Biochemistry Department, Transfer and Molecular Oncology Unit, South Lyon Hospital, Hospices Civils de Lyon, Pierre Bénite, Lyon, France.
Claire
C
Rodriguez-Lafrasse
EMR3738, Equipe de Radiobiologie Cellulaire et Moléculaire, Faculté de Médecine Lyon Sud - Charles Mérieux, Oullins, France.|Université de Lyon, Lyon, France.|“Signalization Metabolism and Tumor Progression” Team, CRCL, INSERM 1052-CNRS 5286,  Lyon, France.|Biochemistry Department, Transfer and Molecular Oncology Unit, South Lyon Hospital, Hospices Civils de Lyon, Pierre Bénite, Lyon, France.
Delphine
D
Poncet
D015720:5'-Nucleotidase / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D034622:RNA Interference
D058851:GPI-Linked Proteins; C574206:MIRN422 microRNA, human; D035683:MicroRNAs; D015720:5'-Nucleotidase; C548241:NT5E protein, human
CD73; HNSCC; miR-422a; personalized medicine