Gene therapy with SOCS1 for gastric cancer induces G2/M arrest and has an antitumour effect on peritoneal carcinomatosis.
Gene therapy with SOCS1 for gastric cancer induces G2/M arrest and has an antitumour effect on peritoneal carcinomatosis.
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DOI：
10.1038/bjc.2015.229
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发表时间：
2015-07-28
影响因子：
8.8
通讯作者：
Naka T
中科院分区：
文献类型：
--
作者：
Natatsuka R;Takahashi T;Serada S;Fujimoto M;Ookawara T;Nishida T;Hara H;Nishigaki T;Harada E;Murakami T;Miyazaki Y;Makino T;Kurokawa Y;Yamasaki M;Miyata H;Nakajima K;Takiguchi S;Kishimoto T;Mori M;Doki Y;Naka T
细胞因子信号传导抑制因子 1 (SOCS1) 是多种细胞因子的负调节因子。最近，它被研究作为多种癌症的治疗靶点。然而，如果不考虑增殖信号传导的抑制，就无法完全解释所观察到的 SOCS1 的抗肿瘤作用。我们的目的是发现 SOCS1 对胃癌 (GC) 的抗肿瘤作用的新机制。我们分析了SOCS1的体外抗肿瘤作用机制。此外，我们在临床前环境中使用异种移植腹膜癌病小鼠模型评估了 GC 的抗肿瘤作用。我们证实 SOCS1 抑制了五分之四的 GC 细胞系的增殖。 SOCS1 似乎通过一种涉及 G2/M 检查点细胞周期调节的新机制来阻止增殖。我们发现 SOCS1 通过与共济失调毛细血管扩张和 Rad3 相关蛋白的相互作用影响细胞周期相关分子。治疗效果的显着差异体现在腹腔内肿瘤的治疗后重量和总光子计数方面。 SOCS1的强制表达揭示了一种迄今为止未知的细胞周期调节机制，并可能代表一种治疗胃癌腹膜癌病的新方法。
Suppressor of cytokine signaling1 (SOCS1) is a negative regulator of various cytokines. Recently, it was investigated as a therapeutic target in various cancers. However, the observed antitumour effects of SOCS1 cannot not be fully explained without taking inhibition of proliferation signalling into account. Our aim was to discover a new mechanism of antitumour effects of SOCS1 for gastric cancer (GC). We analysed the mechanism of antitumour effect of SOCS1 in vitro. In addition, we evaluated antitumour effect for GC using a xenograft peritoneal carcinomatosis mouse model in preclinical setting. We confirmed that SOCS1 suppressed proliferation in four out of five GC cell lines. SOCS1 appeared to block proliferation by a new mechanism that involves cell cycle regulation at the G2/M checkpoint. We showed that SOCS1 influenced cell cycle-associated molecules through its interaction with ataxia telangiectasia and Rad3-related protein. The significant difference in therapeutic effects was noted in terms of the post-treatment weight and total photon count of the intra-abdominal tumours. Forced expression of SOCS1 revealed a heretofore-unknown mechanism for regulating the cell cycle and may represent a novel therapeutic approach for the treatment of peritoneal carcinomatosis of GC.