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Abstract
Abstract Objective: The peritoneal metastasis is one of the most common recurrence style of gastric cancer (GC) and an effective treatment for their patients has not been established. Suppressor of cytokine signaling-1 (SOCS-1) is a negative regulator of various cytokine signaling and has been recently focused on as a therapeutic target in treatment for cancer. The aim of this study was to evaluate the effect with the enforced SOCS-1 expression by adenoviral vector (AdSOCS-1). METHODS: We evaluated the therapeutic effect of SOCS-1 in 6 GC cell lines with proliferation assay. Moreover, we examined the mechanism of antitumor effect of SOCS-1 focusing on the cell signalling and cell cycle in vitro. In vivo study, we evaluated the therapeutic effect in mice model. MKN45-Luc cell line was intraperitoneally injected into ICR nu/nu mice. And, we evaluated the peritoneal dissemination by the in vivo imaging system using Xenogen IVIS ® Imaging System. We treated these mice using the intraperitoneal injection of AdSOCS-1, twice a week for 4weeks. We evaluated the peritoneum dissemination by the photon intensity with time course repeatedly. Finally, we examined these tumor specimen pathologically and the overall survival (N=22). RESULTS: In 3 GC cell lines among 6 GC cell lines, AdSOCS-1 suppressed the proliferation. SOCS-1 showed an anti-proliferative potential in the GC cell proliferation via the inhibition of JAK/STAT and p38 MAPK signaling pathways and also induced apoptosis in vitro. Additionally, SOCS-1 is proven to influence the cell cycle in G2/M phase activating the Chk2 in a JAK/STAT independent manner. In Xenograft peritoneal dissemination model, the total count of photon after therapy in AdSOCS-1 group was significantly lower than that in control group. By TUNEL immunohistochemical analysis, tumor specimen in AdSOCS-1 group included more apoptosis area comparing with that in the control group. To assess whether overexpression of SOCS-1 also reduced proliferation of MKN-45 cells in vivo, Ki-67 expression was determined by immunohistochemistry. AdSOCS-1 group showed decreased Ki-67 positive cells compared to control group. We compared the overall survival of the peritoneal dissemination mice in two groups. AdSOCS-1 group showed better outcome than control group significantly. CONCLUSIONS: Our results indicated that SOCS-1 inhibited the progression of gastric cancer in Xenograft peritoneal dissemination model. SOCS-1 can be a novel therapeutic application for peritoneal metastasis in gastric cancer. Citation Format: Rie Nakatsuka, Tsuyoshi Takahashi, Satoshi Serada, Minoru Fujimoto, Yoshihito Souma, Yasuhiro Miyazaki, Yukinori Kurokawa, Makoto Yamasaki, Hiroshi Miyata, Kiyokazu Nakajima, Shuji Takiguchi, Masaki Mori, Yuichiro Doki, Yuichiro Doki, Tetsuji Naka. Gene therapy for peritoneal dissemination model of gastric cancer using SOCS-1 by Adenoviral Vector. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 722. doi:10.1158/1538-7445.AM2014-722
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