Research Papers:

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

Alexandre Bozec, Joséphine Zangari, Mathilde Butori-Pepino, Marius Ilie, Salomé Lalvee, Thierry Juhel, Catherine Butori, Patrick Brest, Paul Hofman and Valérie Vouret-Craviari _

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Oncotarget. 2017; 8:57174-57186. https://doi.org/10.18632/oncotarget.19170

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Alexandre Bozec1,2,5, Joséphine Zangari1, Mathilde Butori-Pepino1, Marius Ilie1,3,4,5, Salomé Lalvee3, Thierry Juhel1, Catherine Butori3,4, Patrick Brest1,5, Paul Hofman1,3,4,5,* and Valérie Vouret-Craviari1,5,*

1Université Côte d’Azur, INSERM, CNRS, IRCAN, Nice, France

2Head and Neck University Institute, Nice, France

3Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, Nice, France

4Hospital-Related Biobank (BB-0033-00025), Pasteur Hospital, Nice, France

5FHU OncoAge, Nice, France

*These authors contributed equally to this work

Correspondence to:

Valérie Vouret-Craviari, email: [email protected]

Keywords: MiRs, tumors, neutrophils, inflammation, anticancer agents

Received: December 21, 2016     Accepted: June 29, 2017     Published: July 11, 2017


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.

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