| RRC ID |
65056
|
| 著者 |
Sugase T, Takahashi T, Serada S, Fujimoto M, Hiramatsu K, Ohkawara T, Tanaka K, Miyazaki Y, Makino T, Kurokawa Y, Yamasaki M, Nakajima K, Kishimoto T, Mori M, Doki Y, Naka T.
|
| タイトル |
SOCS1 Gene Therapy Improves Radiosensitivity and Enhances Irradiation-Induced DNA Damage in Esophageal Squamous Cell Carcinoma.
|
| ジャーナル |
Cancer Res
|
| 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.
|
| 巻・号 |
77(24)
|
| ページ |
6975-6986
|
| 公開日 |
2017-12-15
|
| DOI |
10.1158/0008-5472.CAN-17-1525
|
| PII |
0008-5472.CAN-17-1525
|
| PMID |
29042418
|
| MeSH |
Animals
Apoptosis / genetics
Apoptosis / radiation effects
Carcinoma, Squamous Cell / genetics
Carcinoma, Squamous Cell / radiotherapy
Carcinoma, Squamous Cell / therapy*
Cell Line, Tumor
Combined Modality Therapy
DNA Damage / genetics*
Esophageal Neoplasms / genetics
Esophageal Neoplasms / radiotherapy
Esophageal Neoplasms / therapy*
Esophageal Squamous Cell Carcinoma
Female
Genetic Therapy / methods*
Humans
Mice
Mice, Inbred ICR
Mice, Nude
Radiation Tolerance / genetics*
Radiation, Ionizing
Retrospective Studies
Suppressor of Cytokine Signaling 1 Protein / genetics*
Xenograft Model Antitumor Assays
|
| IF |
9.727
|
| リソース情報 |
| ヒト・動物細胞 |
TE-4(RCB2097)
TE-8(RCB2098)
TE-14(RCB2101) |
