title: STAT3 silencing enhances the efficacy of the HSV.tk suicide gene in gastrointestinal cancer therapy.
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.
authors.affiliation: 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.
authors.forename: Ye-Hyeon
authors.initials: YH
authors.lastname: Ahn
authors.forename: Hwajung
authors.initials: H
authors.lastname: Yi
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Shin
authors.forename: Kang-Duck
authors.initials: KD
authors.lastname: Lee
authors.forename: Seung-Pil
authors.initials: SP
authors.lastname: Shin
authors.forename: Sang-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Jaewhan
authors.initials: J
authors.lastname: Song
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Chun
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000628:therapy*; D020868:Gene Silencing; D041722:Genes, Transgenic, Suicide / Q000235:genetics*; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D050796:STAT3 Transcription Factor / Q000172:deficiency* / Q000235:genetics; D018139:Simplexvirus / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D013937:Thymidine Kinase