STAT3 silencing enhances the efficacy of the HSV.tk suicide gene in gastrointestinal cancer therapy

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• 作者：Ye-Hyeon Ahn (2) (4)
  Hwajung Yi (2)
  Ji-Young Shin (2)
  Kang-Duck Lee (2)
  Seung-Pil Shin (3)
  Sang-Jin Lee (3)
  Jaewhan Song (4)
  Kyung-Hee Chun (1)
  
• 关键词：STAT3 ; Thymidine kinase ; Gene therapy ; Anti ; tumor immune response ; Gastrointestinal cancer
• 刊名：Clinical & Experimental Metastasis
• 出版年：2012
• 出版时间：April 2012
• 年：2012
• 卷：29
• 期：4
• 页码：359-369
• 全文大小：822KB
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• 作者单位：Ye-Hyeon Ahn (2) (4)
  Hwajung Yi (2)
  Ji-Young Shin (2)
  Kang-Duck Lee (2)
  Seung-Pil Shin (3)
  Sang-Jin Lee (3)
  Jaewhan Song (4)
  Kyung-Hee Chun (1)
  
  2. Gastric Cancer Branch, Division of Translational & Clinical Research I, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410-769, Republic of Korea
  4. Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
  3. Genitourinary Cancer Branch, Division of Translational & Clinical Research II, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea
  1. Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 250 Sungsan-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea
  
• ISSN：1573-7276

文摘

Aberrant activation of Signal Transducer and Activator of Transcription 3 (STAT3) signaling has been shown to be associated with uncontrolled cell proliferation and suppression of host-immune surveillance. Conversely, silencing STAT3 can have the dual effects of inhibiting cancer cell proliferation and inducing anti-tumor immune responses. Here, we report on the effects of STAT3 silencing on suicide gene therapy with thymidine kinase (tk). STAT3 silencing by siRNA inhibited the proliferation of AGS human gastric cancer cells through G1 cell cycle arrest, decreased levels of immune-suppressive cytokines, and increased levels of immune-activating cytokines. CT26 mouse colon adenocarcinoma cells, in which STAT3 expression was knocked-down by a STAT3 shRNA-containing lentivirus, grew more slowly in syngenic model Balb/c mice than control CT26 cells. Moreover, we found that STAT3 silencing augmented the efficacy of suicide gene therapy in CT26 cell xenografted mice. When we administrated adenoviruses harboring the herpes simplex virus thymidine kinase gene (Ad5.CMV.HSV.tk) into STAT3-silenced CT26 cell tumors, extensive apoptosis was observed and there was a significant reduction in the size of CT26 cell tumors. STAT3 silencing also enhanced the recruitment and cytotoxic activity of CD3+CD8+ T-cells, and changed the cytokine expression pattern of CT26 cell tumors, reflecting augmentation of anti-cancer immune responses. We conclude that combining suicide gene therapy with STAT3 silencing can result in enhanced anti-cancer effects.