Antitumor effects of Stat3-siRNA and endostatin combined therapies, delivered by attenuated Salmonella, on orthotopically implanted hepatocarcinoma

被引:63
作者
Jia, Huijie [1 ]
Li, Yang [1 ]
Zhao, Tiesuo [2 ]
Li, Xin [1 ]
Hu, Jiadi [3 ]
Yin, Di [1 ]
Guo, Baofeng [1 ]
Kopecko, Dennis J. [4 ]
Zhao, Xuejian [1 ]
Zhang, Ling [1 ]
Xu, De Qi [5 ]
机构
[1] Jilin Univ, Dept Pathophysiol, Prostate Dis Prevent & Treatment Res Ctr, Norman Bethune Coll Med, Changchun 130021, Peoples R China
[2] Jilin Univ, Dept Immunol, Norman Bethune Med Sch, Changchun 130021, Peoples R China
[3] Univ Maryland, Sch Dent, Dept Oncol & Diagnost Sci, Baltimore, MD 21201 USA
[4] US FDA, Lab Enter & Sexually Transmitted Dis, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA
[5] Beijing Three Room S 4 Hosp, New Vaccine Natl Engn Res Ctr, Beijing 100024, Peoples R China
基金
高等学校博士学科点专项科研基金; 中国国家自然科学基金;
关键词
Combined gene therapy; Hepatocellular carcinoma; RNA interference; Anti-angiogenesis; Immune response; REGULATORY T-CELLS; HEPATOCELLULAR-CARCINOMA; MOLECULAR TARGETS; TUMOR-GROWTH; EXPRESSION; CANCER; ANGIOGENESIS; TYPHIMURIUM; SUPPRESSION; METASTASIS;
D O I
10.1007/s00262-012-1256-y
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:1977 / 1987
页数:11
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