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

Authors
 Ye-Hyeon Ahn  ;  Hwajung Yi  ;  Ji-Young Shin  ;  Kang-Duck Lee  ;  Seung-Pil Shin  ;  Sang-Jin Lee  ;  Jaewhan Song  ;  Kyung-Hee Chun 
Citation
 CLINICAL & EXPERIMENTAL METASTASIS, Vol.29(4) : 359-369, 2012 
Journal Title
CLINICAL & EXPERIMENTAL METASTASIS
ISSN
 0262-0898 
Issue Date
2012
MeSH
Animals ; Apoptosis/genetics ; Cell Line, Tumor ; Gastrointestinal Neoplasms/genetics ; Gastrointestinal Neoplasms/therapy* ; Gene Silencing ; Genes, Transgenic, Suicide/genetics* ; Genetic Therapy* ; Humans ; Mice ; STAT3 Transcription Factor/deficiency* ; STAT3 Transcription Factor/genetics ; Simplexvirus/genetics* ; Thymidine Kinase/genetics ; Thymidine Kinase/metabolism* ; Transplantation, Heterologous ; Xenograft Model Antitumor Assays
Keywords
STAT3 ; Thymidine kinase ; Gene therapy ; Anti-tumor immune response ; Gastrointestinal cancer
Abstract
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.
Full Text
http://link.springer.com/article/10.1007%2Fs10585-012-9458-4
DOI
22350508
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Chun, Kyung Hee(전경희) ORCID logo https://orcid.org/0000-0002-9867-7321
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/89985
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