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

Nathalie Bonnin,Sébastien Guihard,Sylvain Ferrandon,Priscillia Battiston-Montagne,Alain Jung,Marc Aubry,Jean-Philippe Foy,Sonia Ledrappier,Pierre Saintigny,David Meyronet,Emma Armandy,Claire Rodriguez-Lafrasse,Ruth Rimokh,Delphine Poncet,Julien Carras

doi:10.18632/oncotarget.9829

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.

Highlights

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide
In the present study we have demonstrated that miR-422a expression is significantly downregulated in oropharynx tumors from patients who have experienced early loco(regional) recurrence, as well as in tumor compared to normal tissues
We have shown that the mRNA, protein and enzymatic activity of the CD73 nucleotidase, which is involved in the oncogenic processes, are modulated by miR-422a, and that CD73 downregulation mimics the effects of miR422a overexpression

Summary

Introduction

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Dose de-escalation could be envisaged for patients with a good-predicted outcome to reduce the frequency of debilitating side effects (difficulties in swallowing, breathing, eating...), induced by the standard treatment In this field, the Human Papilloma Virus (HPV) infection - known to be predictive of good outcome - is more and more considered as a marker for dose de-escalation, with encouraging results considering reduced toxicity (NCT01530997). Extensive genomic and transcriptomic (meta)analyses have characterized four [7] (revised to six [8]) molecular subclasses of HNSCC: Basal, Classical, Mesenchymal and Atypical [7] This signature has paved the way for the development of personalized treatments, but cannot, as such, be translated into clinical routine tests. To conclude, regarding clinical practices, the challenge is no longer to identify global prognosis/predictive markers to prescribe intensified treatments based on standard chemo-radiotherapy approaches, but instead as Kang et al proposed, to identify novel therapeutic targets and to develop predictive companion biomarkers [6]

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