Suppressor of cytokine signaling-1 gene therapy induces potent antitumor effect in patient-derived esophageal squamous cell carcinoma xenograft mice
| Autor: | Koji Tanaka, Rie Nakatsuka, Tetsuji Naka, Hisashi Hara, Kiyokazu Nakajima, Shuji Takiguchi, Yukinori Kurokawa, Takahiko Nishigaki, Tomoharu Ohkawara, Masaki Mori, Tadamitsu Kishimoto, Yuichiro Doki, Tsuyoshi Takahashi, Minoru Fujimoto, Tomoki Makino, Makoto Yamasaki, Yasuhiro Miyazaki, Takahito Sugase, Satoshi Serada |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Suppressor of cytokine signaling 1 Genetic enhancement Cancer Biology medicine.disease digestive system diseases 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology 030220 oncology & carcinogenesis SOCS1 Gene STAT protein Cancer research medicine Gene silencing Signal transduction Janus kinase neoplasms |
| Zdroj: | International Journal of Cancer. 140:2608-2621 |
| ISSN: | 0020-7136 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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