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

Takahito Sugase,Yasuhiro Miyazaki,Tadamitsu Kishimoto,Yukinori Kurokawa,Yuichiro Doki,Kiyokazu Nakajima,Tetsuji Naka,Tsuyoshi Takahashi,Tomoharu Ohkawara,Tomoki Makino,Masaki Mori,Kosuke Hiramatsu,Koji Tanaka,Satoshi Serada,Makoto Yamasaki,Minoru Fujimoto

doi:10.1158/0008-5472.can-17-1525

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. Cancer Res; 77(24); 6975-86. ©2017 AACR.

Highlights

Esophageal cancer is the eighth most common cancer and the sixth most common cause of cancer-related mortality in the world [1]
We examined the expression of p-STAT3 in advanced esophageal squamous cell carcinoma (ESCC) patients who underwent surgery alone or preoperative CRT by immunohistochemistry. p-STAT3 positivity was noted in the nuclei
There were no significant differences between age, gender, pT, or pStage (UICC 7th edition) and STAT3 expression in ESCC patients who underwent preoperative CRT (Table 1)

Summary

Introduction

Esophageal cancer is the eighth most common cancer and the sixth most common cause of cancer-related mortality in the world [1]. In Asia, esophageal squamous cell carcinoma (ESCC) is the predominant histologic form of esophageal cancer. Multimodal treatments, including surgery, radiotherapy, and chemotherapy are currently used, patients with ESCC still face with poor prognosis [2, 3]. Definitive chemoradiotherapy (CRT) is a standard treatment option for locally advanced or unresectable ESCC [4, 5]. Locoregional recurrence after CRT is observed in 40% to 60% of patients [6, 7]. Salvage surgery after CRT is associated with a high complication rate (50%–77%) and high

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Conclusion