SOCS1 Gene Therapy Improves Radiosensitivity and Enhances Irradiation-Induced DNA Damage in Esophageal Squamous Cell Carcinoma

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 24; pp. 6975 - 6986
• Main Authors: Sugase, Takahito, Takahashi, Tsuyoshi, Serada, Satoshi, Fujimoto, Minoru, Hiramatsu, Kosuke, Ohkawara, Tomoharu, Tanaka, Koji, Miyazaki, Yasuhiro, Makino, Tomoki, Kurokawa, Yukinori, Yamasaki, Makoto, Nakajima, Kiyokazu, Kishimoto, Tadamitsu, Mori, Masaki, Doki, Yuichiro, Naka, Tetsuji
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research, Inc 15.12.2017
• Subjects: Animals; Antitumor activity; Apoptosis; Apoptosis - genetics; Apoptosis - radiation effects; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - radiotherapy; Carcinoma, Squamous Cell - therapy; Cell Line, Tumor; Chemoradiotherapy; Combined Modality Therapy; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - genetics; Esophageal cancer; Esophageal Neoplasms - genetics; Esophageal Neoplasms - radiotherapy; Esophageal Neoplasms - therapy; Esophageal Squamous Cell Carcinoma; Esophagus; Female; Gene therapy; Genetic Therapy - methods; Humans; Irradiation; Mcl-1 protein; Mice; Mice, Inbred ICR; Mice, Nude; Proteins; Radiation; Radiation therapy; Radiation Tolerance - genetics; Radiation, Ionizing; Radioresistance; Radiosensitivity; Repopulation; Retrospective Studies; Squamous cell carcinoma; Stat3 protein; Suppressor of Cytokine Signaling 1 Protein - genetics; Surgery; Survivin; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-17-1525

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 with 9 of 24 patients with surgery alone, where the prognosis of those with CRT was poor. Expression of p-STAT3 and the antiapoptotic 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 with 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 γH2AX 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. .