Antitumor effects of Stat3-siRNA and endostatin combined therapies, delivered by attenuated Salmonella, on orthotopically implanted hepatocarcinoma
Antitumor effects of Stat3-siRNA and endostatin combined therapies, delivered by attenuated Salmonella, on orthotopically implanted hepatocarcinoma
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DOI：
10.1007/s00262-012-1256-y
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发表时间：
2012-11-01
影响因子：
5.8
通讯作者：
Xu, De Qi
中科院分区：
文献类型：
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作者：
Jia, Huijie;Li, Yang;Xu, De Qi
肝细胞癌（HCC）是最具侵袭性的癌症之一。有限的治疗选择，主要是由于对HCC的遗传理解不完整，以及HCC对常规化疗的主要耐药性是预后不良的关键原因。因此，新的有效的治疗方法是迫切的，基因治疗可能是一个新的选择。信号转导子和转录激活子3（Stat 3）是STAT家族的一个高度研究的成员。已经发现抑制Stat 3信号传导可以抑制肿瘤生长并提高存活率，为癌症治疗提供了分子靶点。此外，HCC是一种多血管肿瘤，血管生成在肿瘤生长和转移中起着至关重要的作用。因此，抗血管生成治疗结合Stat 3的抑制可能是对抗HCC的有效方法。我们测试了由内皮抑素（一种强大的血管生成抑制剂）和Stat 3特异性小干扰RNA组成的联合治疗的效果，使用由减毒S.在C57 BL/6小鼠的原位HCC模型上，尽管任一单一治疗均观察到抗肿瘤作用，但联合治疗具有上级抗肿瘤作用。与此相关的是，联合治疗导致Stat 3和内皮抑素水平以及下游基因VEGF水平的显著改变，降低细胞增殖，诱导细胞凋亡并抑制血管生成。重要的是，联合治疗还引起免疫系统对各种免疫细胞和细胞因子的调节。本研究为肿瘤的基因治疗提供了新的途径。
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.