SOCS1 gene therapy improves radiosensitivity and enhances irradiation-induced DNA damage in esophageal squamous cell carcinoma

Menée à l'aide de lignées cellulaires de carcinome épidermoïde de l'œsophage, d'échantillons tumoraux fixés au formaldéhyde et inclus en paraffine après prélèvement, de xénogreffes sur un modèle murin et de données clinico-pathologiques portant sur 46 patients, cette étude montre qu'une thérapie génique, utilisant un adénovirus modifié exprimant SOCS1 (une protéine régulant l'expression de STAT3), augmente la sensibilité des cellules tumorales aux rayonnements ionisants ainsi que les dommages causés à l'ADN tumoral

Résumé en anglais

STAT3 has been implicated recently in radioresistance in cancer. In this study, we investigated the association between STAT3 and radioresistance in esophageal squamous cell carcinoma (ESCC). Strong expression of activated phospho-STAT3 (p-STAT3) was observed in 16/22 ESCC patients with preoperative chemoradiotherapy (CRT), compared to 9/24 patients with surgery alone, where the prognosis of those with CRT was poor. Expression of p-STAT3 and the anti-apoptotic proteins Mcl-1 and survivin was strongly induced in ESCC cells by irradiation. Ectopic STAT3 expression increased radioresistance, whereas expression of the STAT3 negative regulator SOCS1 via an adenoviral vector improved radioresponse. Inhibiting the STAT3-Mcl-1 axis by SOCS1 enhanced DNA damage after irradition and induced apoptosis. Combining SOCS1 with radiotherapy enhanced antitumor responses in a murine xenograft model compared to the individual therapies. Tumor repopulation occurred transiently after treatment by irradiation but not the combination SOCS1/radiotherapy. Tumors subjected to this combination expressed high levels of γ-H2AX and low levels of Ki-67, which was maintained after cessation of treatment. Overall, we demonstrated that inhibiting the STAT3-Mcl-1 signaling axis by ectopic SOCS1 improved radiosensitivity by inducing apoptosis and enhancing DNA damage after radiotherapy, offering a mechanistic rationale for a new ESCC treatment.