TY - JOUR
T1 - SOCS1 gene therapy improves radiosensitivity and enhances irradiation-induced DNA damage in esophageal squamous cell carcinoma
AU - Sugase, Takahito
AU - Takahashi, Tsuyoshi
AU - Serada, Satoshi
AU - Fujimoto, Minoru
AU - Hiramatsu, Kosuke
AU - Ohkawara, Tomoharu
AU - Tanaka, Koji
AU - Miyazaki, Yasuhiro
AU - Makino, Tomoki
AU - Kurokawa, Yukinori
AU - Yamasaki, Makoto
AU - Nakajima, Kiyokazu
AU - Kishimoto, Tadamitsu
AU - Mori, Masaki
AU - Doki, Yuichiro
AU - Naka, Tetsuji
N1 - Funding Information:
This research was partially supported by Research for Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development, AMED (15ck0106106h0002 to T. Naka).
Publisher Copyright:
2017 American Association for Cancer Research.
PY - 2017
Y1 - 2017
N2 - 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 gH2AX 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.
AB - 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 gH2AX 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.
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U2 - 10.1158/0008-5472.CAN-17-1525
DO - 10.1158/0008-5472.CAN-17-1525
M3 - Article
C2 - 29042418
AN - SCOPUS:85038570672
SN - 0008-5472
VL - 77
SP - 6975
EP - 6986
JO - Cancer Research
JF - Cancer Research
IS - 24
ER -
