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

Abstract

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.

• Authors: Takahito Sugase, Tsuyoshi Takahashi, Satoshi Serada, Rie Nakatsuka, Minoru Fujimoto, Tomoharu Ohkawara, Hisashi Hara, Takahiko Nishigaki, Koji Tanaka, Yasuhiro Miyazaki, Tomoki Makino, Yukinori Kurokawa, Makoto Yamasaki, Kiyokazu Nakajima, Shuji Takiguchi, Tadamitsu Kishimoto, Masaki Mori, Yuichiro Doki, Tetsuji Naka
• Journal: International journal of cancer (Int J Cancer) Vol. 140 Issue 11 Pg. 2608-2621 (06 01 2017) ISSN: 1097-0215 [Electronic] United States
• PMID: 28233302 (Publication Type: Journal Article)
• Copyright: © 2017 UICC.

Chemical References

• Antineoplastic Agents
• SOCS1 protein, human
• Suppressor of Cytokine Signaling 1 Protein
• Janus Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, genetics)
• Carcinoma, Squamous Cell (drug therapy, genetics)
• Cell Line, Tumor
• Cell Proliferation (drug effects, genetics)
• Esophageal Neoplasms (drug therapy, genetics)
• Esophageal Squamous Cell Carcinoma
• Female
• Genetic Therapy (methods)
• Humans
• Janus Kinases (genetics)
• Mice
• Mice, Inbred ICR
• Mice, Nude
• Signal Transduction (drug effects, genetics)
• Suppressor of Cytokine Signaling 1 Protein (genetics, pharmacology)
• Xenograft Model Antitumor Assays (methods)