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Abstract

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.

Author information

Sugase T1,2,3, Takahashi T4,2, Serada S2,3, Fujimoto M2,3, Hiramatsu K2,3, Ohkawara T2,3, Tanaka K1, Miyazaki Y1, Makino T1, Kurokawa Y1, Yamasaki M1, Nakajima K1, Kishimoto T5, Mori M1, Doki Y1, Naka T6,3.
1
Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.
2
Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan.
3
Center for Intractable Immune Disease, Kochi University, Nankoku, Japan.
4
Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan. ttakahashi2@gesurg.med.osaka-u.ac.jp naka@kochi-u.ac.jp.
5
Laboratory of Immune Regulation, Osaka University Graduate School of Frontier Biosciences, Osaka, Japan.
6
Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan. ttakahashi2@gesurg.med.osaka-u.ac.jp naka@kochi-u.ac.jp.