Suppressor of cytokine signaling-1 gene therapy induces potent antitumor effect in patient-derived esophageal squamous cell carcinoma xenograft mice

被引：38

作者：

Sugase, Takahito ^{[1
,2
]}

Takahashi, Tsuyoshi ^{[1
,2
]}

Serada, Satoshi ^{[2
]}

Nakatsuka, Rie ^{[1
,2
]}

Fujimoto, Minoru ^{[2
]}

Ohkawara, Tomoharu ^{[2
]}

Hara, Hisashi ^{[1
,2
]}

Nishigaki, Takahiko ^{[1
,2
]}

Tanaka, Koji ^{[1
]}

Miyazaki, Yasuhiro ^{[1
]}

Makino, Tomoki ^{[1
]}

Kurokawa, Yukinori ^{[1
]}

Yamasaki, Makoto ^{[1
]}

Nakajima, Kiyokazu ^{[1
]}

Takiguchi, Shuji ^{[1
]}

Kishimoto, Tadamitsu ^{[3
]}

Mori, Masaki ^{[1
]}

Doki, Yuichiro ^{[1
]}

Naka, Tetsuji ^{[2
]}

机构：

[1] Osaka Univ, Dept Surg Gastroenterol, Grad Sch Med, Suita, Osaka, Japan

[2] Natl Inst Biomed Innovat Hlth & Nutr, Lab Immune Signal, 7-6-8 Saito Asagi, Ibaraki, Osaka 5670085, Japan

[3] Osaka Univ, Lab Immune Regulat, Grad Sch Frontier Biosci, Osaka, Japan

来源：

INTERNATIONAL JOURNAL OF CANCER | 2017年 / 140卷 / 11期

关键词：

esophageal squamous cell cancer; suppressor of cytokine signaling; signal transducer and activator of transcription 3; patient-derived xenograft model; ADENOVIRUS RECEPTOR; GROWTH-SUPPRESSION; CANCER; CHEMORADIOTHERAPY; EXPRESSION; PROTEIN; STAT3; PROLIFERATION; SURVIVAL; SOCS-1;

D O I：

10.1002/ijc.30666

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Chronic inflammation is involved in cancer growth in esophageal squamous cell carcinoma (ESCC), which is a highly refractory cancer with poor prognosis. This study investigated the antitumor effect and mechanisms of SOCS1 gene therapy for ESCC. Patients with ESCC showed epigenetics silencing of SOCS1 gene by methylation in the CpG islands. We infected 10 ESCC cells with an adenovirus-expressing SOCS1 (AdSOCS1) to examine the antitumor effect and mechanism of SOCS1 overexpression. SOCS1 overexpression markedly decreased the proliferation of all ESCC cell lines and induced apoptosis. Also, SOCS1 inhibited the proliferation of ESCC cells via multiple signaling pathways including Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and focal adhesion kinase (FAK)/p44/42 mitogen-activated protein kinase (p44/42 MAPK). Additionally, we established two xenograft mouse models in which TE14 ESCC cells or ESCC patient-derived tissues (PDX) were subcutaneously implanted. Mice were intra-tumorally injected with AdSOCS1 or control adenovirus vector (AdLacZ). In mice, tumor volumes and tumor weights were significantly lower in mice treated with AdSOCS1 than that with AdLacZ as similar mechanism to the in vitro findings. The Ki-67 index of tumors treated with AdSOCS1 was significantly lower than that with AdLacZ, and SOCS1 gene therapy induced apoptosis. These findings demonstrated that overexpression of SOCS1 has a potent antitumor effect against ESCC both in vitro and in vivo including PDX mice. SOCS1 gene therapy may be a promising approach for the treatment of ESCC. What's new? Chronic inflammation is thought to play a role in esophageal squamous cell carcinoma (ESCC). A protein called SOCS1 reduces inflammatory signaling, and the gene for SOCS1 is inactivated in many ESCC tumors. In this study, the authors found that, when SOCS1 levels were increased in mice via gene therapy, the proliferation of ESCC xenografts decreased, and apoptosis was induced in these cells via several pathways. SOCS1 gene therapy may thus be a promising approach for the treatment of ESCC.

引用

页码：2608 / 2621

页数：14

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[1] Chemoradiotherapy and surgery for T4 esophageal cancer in Japan [J].