TY - JOUR
T1 - miR-9 modulates and predicts the response to radiotherapy and EGFR inhibition in HNSCC
AU - Citron, Francesca
AU - Segatto, Ilenia
AU - Musco, Lorena
AU - Pellarin, Ilenia
AU - Rampioni Vinciguerra, Gian Luca
AU - Franchin, Giovanni
AU - Fanetti, Giuseppe
AU - Miccichè, Francesco
AU - Giacomarra, Vittorio
AU - Lupato, Valentina
AU - Favero, Andrea
AU - Concina, Isabella
AU - Srinivasan, Sanjana
AU - Avanzo, Michele
AU - Castiglioni, Isabella
AU - Barzan, Luigi
AU - Sulfaro, Sandro
AU - Petrone, Gianluigi
AU - Viale, Andrea
AU - Draetta, Giulio F.
AU - Vecchione, Andrea
AU - Belletti, Barbara
AU - Baldassarre, Gustavo
N1 - Publisher Copyright:
© 2021 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2021/7/7
Y1 - 2021/7/7
N2 - Radiotherapy (RT) plus the anti-EGFR monoclonal antibody Cetuximab (CTX) is an effective combination therapy for a subset of head and neck squamous cell carcinoma (HNSCC) patients. However, predictive markers of efficacy are missing, resulting in many patients treated with disappointing results and unnecessary toxicities. Here, we report that activation of EGFR upregulates miR-9 expression, which sustains the aggressiveness of HNSCC cells and protects from RT-induced cell death. Mechanistically, by targeting KLF5, miR-9 regulates the expression of the transcription factor Sp1 that, in turn, stimulates tumor growth and confers resistance to RT+CTX in vitro and in vivo. Intriguingly, high miR-9 levels have no effect on the sensitivity of HNSCC cells to cisplatin. In primary HNSCC, miR-9 expression correlated with Sp1 mRNA levels and high miR-9 expression predicted poor prognosis in patients treated with RT+CTX. Overall, we have discovered a new signaling axis linking EGFR activation to Sp1 expression that dictates the response to combination treatments in HNSCC. We propose that miR-9 may represent a valuable biomarker to select which HNSCC patients might benefit from RT+CTX therapy.
AB - Radiotherapy (RT) plus the anti-EGFR monoclonal antibody Cetuximab (CTX) is an effective combination therapy for a subset of head and neck squamous cell carcinoma (HNSCC) patients. However, predictive markers of efficacy are missing, resulting in many patients treated with disappointing results and unnecessary toxicities. Here, we report that activation of EGFR upregulates miR-9 expression, which sustains the aggressiveness of HNSCC cells and protects from RT-induced cell death. Mechanistically, by targeting KLF5, miR-9 regulates the expression of the transcription factor Sp1 that, in turn, stimulates tumor growth and confers resistance to RT+CTX in vitro and in vivo. Intriguingly, high miR-9 levels have no effect on the sensitivity of HNSCC cells to cisplatin. In primary HNSCC, miR-9 expression correlated with Sp1 mRNA levels and high miR-9 expression predicted poor prognosis in patients treated with RT+CTX. Overall, we have discovered a new signaling axis linking EGFR activation to Sp1 expression that dictates the response to combination treatments in HNSCC. We propose that miR-9 may represent a valuable biomarker to select which HNSCC patients might benefit from RT+CTX therapy.
KW - EGFR inhibitors
KW - HNSCC
KW - KLF5
KW - Sp1
KW - radiotherapy
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UR - http://www.scopus.com/inward/citedby.url?scp=85107261353&partnerID=8YFLogxK
U2 - 10.15252/emmm.202012872
DO - 10.15252/emmm.202012872
M3 - Article
C2 - 34062049
AN - SCOPUS:85107261353
SN - 1757-4676
VL - 13
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 7
M1 - e12872
ER -