title: Antitumor effects of Stat3-siRNA and endostatin combined therapies, delivered by attenuated Salmonella, on orthotopically implanted hepatocarcinoma.
abstract: Hepatocellular carcinoma (HCC) is one of the most aggressive carcinomas. Limited therapeutic options, mainly due to a fragmented genetic understanding of HCC, and major HCC resistance to conventional chemotherapy are the key reasons for a poor prognosis. Thus, new effective treatments are urgent and gene therapy may be a novel option. Signal transducer and activator of transcription 3 (Stat3) is a highly studied member of the STAT family. Inhibition of Stat3 signaling has been found to suppress tumor growth and improve survival, providing a molecular target for cancer therapy. Furthermore, HCC is a hypervascular tumor and angiogenesis plays a crucial role in tumor growth and metastasis. Thus, anti-angiogenic therapy, combined with inhibition of Stat3, may be an effective approach to combat HCC. We tested the effect that the combination therapy consisting of endostatin (a powerful angiogenesis inhibitor) and Stat3-specific small interfering RNA, using a DNA vector delivered by attenuated S. typhimurium, on an orthotopic HCC model in C57BL/6 mice. Although antitumor effects were observed with either single therapeutic treatment, the combination therapy provided superior antitumor effects. Correlated with this finding, the combination treatment resulted in significant alteration of Stat3 and endostatin levels and that of the downstream gene VEGF, decreased cell proliferation, induced cell apoptosis and inhibited angiogenesis. Importantly, combined treatment also elicited immune system regulation of various immune cells and cytokines. This study has provided a novel cancer gene therapeutic approach.
authors.affiliation: Department of Pathophysiology, Prostate Diseases Prevention and Treatment Research Centre, Norman Bethune College of Medicine, Jilin University, Changchun, 130021, People's Republic of China.
authors.forename: Huijie
authors.initials: H
authors.lastname: Jia
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Tiesuo
authors.initials: T
authors.lastname: Zhao
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Jiadi
authors.initials: J
authors.lastname: Hu
authors.forename: Di
authors.initials: D
authors.lastname: Yin
authors.forename: Baofeng
authors.initials: B
authors.lastname: Guo
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Kopecko
authors.forename: Xuejian
authors.initials: X
authors.lastname: Zhao
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: De Qi
authors.initials: DQ
authors.lastname: Xu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D043169:Endostatins / Q000235:genetics*; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D008113:Liver Neoplasms / Q000628:therapy*; D008114:Liver Neoplasms, Experimental / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000628:therapy; D034741:RNA, Small Interfering / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D012486:Salmonella typhimurium; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
chemical_list: D043169:Endostatins; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D042461:Vascular Endothelial Growth Factor A