MiR-223-3p inhibits angiogenesis and promotes resistance to cetuximab in head and neck squamous cell carcinoma

// Alexandre Bozec 1, 2, 5 , Josephine Zangari 1 , Mathilde Butori-Pepino 1 , Marius Ilie 1, 3, 4, 5 , Salome Lalvee 3 , Thierry Juhel 1 , Catherine Butori 3, 4 , Patrick Brest 1, 5 , Paul Hofman 1, 3, 4, 5, * and Valerie Vouret-Craviari 1, 5, * 1 Universite Cote d’Azur, INSERM, CNRS, IRCAN, Nice, France 2 Head and Neck University Institute, Nice, France 3 Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, Nice, France 4 Hospital-Related Biobank (BB-0033-00025), Pasteur Hospital, Nice, France 5 FHU OncoAge, Nice, France * These authors contributed equally to this work Correspondence to: Valerie Vouret-Craviari, email: vouret@unice.fr Keywords: MiRs, tumors, neutrophils, inflammation, anticancer agents Received: December 21, 2016      Accepted: June 29, 2017      Published: July 11, 2017 ABSTRACT MicroRNAs (miRs) participate in tumor growth and dissemination by regulating expression of various target genes. MiR-223-3p is suspected of being involved in head and neck squamous cell carcinoma (HNSCC) growth although its precise role has not been elucidated. In this study, we showed that miR-223-3p is present in biopsies of HNSCC patients and that its presence is correlated with high neutrophil infiltrate. We found that overexpression of miR-223-3p slightly increased proliferation of the CAL27 squamous carcinoma cell line both in vitro and in vivo . Moreover, miR-223-3p induced CAL27 apoptosis in an orthotopic xenograft mouse model, counteracting the proliferative effect and resulting in no impact on overall tumor growth. We analyzed the effect of miR-223-3p overexpression on signaling pathways and showed that it induced pERK2, pAKT and AKT, consistent with an increase in cell proliferation. In addition, we found that miR-223-3p reduced the STAT3 level correlating with increased cell apoptosis and inhibited vasculature formation. In HNSCC tissues, miR-223-3p expression was inversely correlated to CD31, highlighting the relationship between miR-223 and vessel formation. Finally, we studied the effect of miR-223-3p on response to selected anticancer agents and showed that cells expressing miR-223-3p are more resistant to drugs, notably cetuximab. In conclusion, our study is the first to show the antiangiogenic properties of miR-223-3p in HNSCC patients and to question whether expression levels of miR-223-3p can be evaluated as an indicator of eligibility for non-treatment of HNSCC patients with cetuximab.