STAT3 silencing enhances the efficacy of the HSV.tk suicide gene in gastrointestinal cancer therapy
STAT3 silencing enhances the efficacy of the HSV.tk suicide gene in gastrointestinal cancer therapy
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DOI：
10.1007/s10585-012-9458-4
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发表时间：
2012-04-01
影响因子：
4
通讯作者：
Chun, Kyung-Hee
中科院分区：
文献类型：
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作者：
Ahn, Ye-Hyeon;Yi, Hwajung;Chun, Kyung-Hee
信号转导和转录激活因子3(STAT3)信号的异常激活与细胞增殖失控和宿主免疫监视的抑制有关。相反，沉默STAT3具有抑制癌细胞增殖和诱导抗肿瘤免疫反应的双重作用。在这里，我们报告了STAT3沉默在胸苷激酶(Tk)自杀基因治疗中的作用。SiRNA沉默STAT3可通过G1期阻滞抑制AGS人胃癌细胞的增殖，降低免疫抑制细胞因子的水平，增加免疫激活细胞因子的水平。在含有STAT3 shRNA的慢病毒下调STAT3表达的CT26小鼠结肠腺癌细胞中，同基因模型Balb/c小鼠的生长速度慢于对照CT26细胞。此外，我们发现STAT3沉默增强了CT26细胞异种移植小鼠自杀基因治疗的效果。当我们将携带单纯疱疹病毒胸苷激酶基因的腺病毒(Ad5.CMV.HSV.tk)导入STAT3沉默的CT26细胞瘤中时，可以观察到广泛的细胞凋亡，并且CT26细胞瘤的大小显著减小。STAT3沉默还增强了CD3(+)CD8(+)T细胞的募集和细胞毒活性，并改变了CT26细胞肿瘤细胞因子的表达模式，反映了抗癌免疫反应的增强。我们的结论是，结合自杀基因治疗和STAT3沉默可以增强抗癌效果。
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.