Gene therapy with SOCS1 for gastric cancer induces G2/M arrest and has an antitumour effect on peritoneal carcinomatosis

作者：Natatsuka Rie; Takahashi Tsuyoshi^*; Serada Satoshi; Fujimoto Minoru; Ookawara Tomohiro; Nishida Toshirou; Hara Hisashi; Nishigaki Takahiko; Harada Emi; Murakami Takashi; Miyazaki Yasuhiro; Makino Tomoki; Kurokawa Yukinori; Yamasaki Makoto; Miyata Hiroshi; Nakajima Kiyokazu; Takiguchi Shuji; Kishimoto Tadamitsu; Mori Masaki; Doki Yuichiro; Naka Tetsuji

来源：British Journal of Cancer, 2015, 113(3): 433-442.

DOI：10.1038/bjc.2015.229

• gastric cancer
• suppressor of cytokine signalling
• ataxia telangiectasia and Rad3-related protein
• cell cycle arrest
• adenovirus vector
• gene therapy
• peritoneal carcinomatosis

Background: 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).
Methods: 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.
Results: 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 cycleassociated 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.
Conclusion: 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.

• 出版日期2015-7-28