title: 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.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.|Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan.
authors.forename: Takahito
authors.initials: T
authors.lastname: Sugase
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.|Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan.
authors.forename: Tsuyoshi
authors.identifier: 0000-0003-4645-2056
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Serada
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.|Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Nakatsuka
authors.affiliation: Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Fujimoto
authors.affiliation: Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan.
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Ohkawara
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.|Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Hara
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.|Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Nishigaki
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Miyazaki
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Makino
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Kurokawa
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamasaki
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Nakajima
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Takiguchi
authors.affiliation: Laboratory of Immune Regulation, Osaka University Graduate School of Frontier Biosciences, Osaka, Japan.
authors.forename: Tadamitsu
authors.initials: T
authors.lastname: Kishimoto
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.affiliation: Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Naka
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D053612:Janus Kinases / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000235:genetics* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; C108944:SOCS1 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D053612:Janus Kinases
keywords: esophageal squamous cell cancer; patient-derived xenograft model; signal transducer and activator of transcription 3; suppressor of cytokine signaling