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.
| Original language | English |
|---|---|
| Pages (from-to) | 359-369 |
| Number of pages | 11 |
| Journal | Clinical and Experimental Metastasis |
| Volume | 29 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2012 Apr 1 |
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All Science Journal Classification (ASJC) codes
- Oncology
- Cancer Research
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STAT3 silencing enhances the efficacy of the HSV.tk suicide gene in gastrointestinal cancer therapy. / Ahn, Ye Hyeon; Yi, Hwajung; Shin, Ji Young; Lee, Kang Duck; Shin, Seung Pil; Lee, Sang Jin; Song, Jaewhan; Chun, Kyung Hee.
In: Clinical and Experimental Metastasis, Vol. 29, No. 4, 01.04.2012, p. 359-369.Research output: Contribution to journal › Article
TY - JOUR
T1 - STAT3 silencing enhances the efficacy of the HSV.tk suicide gene in gastrointestinal cancer therapy
AU - Ahn, Ye Hyeon
AU - Yi, Hwajung
AU - Shin, Ji Young
AU - Lee, Kang Duck
AU - Shin, Seung Pil
AU - Lee, Sang Jin
AU - Song, Jaewhan
AU - Chun, Kyung Hee
PY - 2012/4/1
Y1 - 2012/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84862824887&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84862824887&partnerID=8YFLogxK
U2 - 10.1007/s10585-012-9458-4
DO - 10.1007/s10585-012-9458-4
M3 - Article
C2 - 22350508
AN - SCOPUS:84862824887
VL - 29
SP - 359
EP - 369
JO - Clinical and Experimental Metastasis
JF - Clinical and Experimental Metastasis
SN - 0262-0898
IS - 4
ER -