A novel oncolytic adenovirus selectively silences the expression of tumor-associated STAT3 and exhibits potent antitumoral activity
A novel oncolytic adenovirus selectively silences the expression of tumor-associated STAT3 and exhibits potent antitumoral activity
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一种新型溶瘤腺病毒选择性沉默肿瘤相关 STAT3 的表达并表现出有效的抗肿瘤活性。
DOI：
10.1093/carcin/bgp249
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发表时间：
2009-12-01
期刊：
影响因子：
4.7
通讯作者：
Ma, Ding
中科院分区：
文献类型：
--
作者：
Han, Zhiqiang;Hong, Zhenya;Ma, Ding
肿瘤细胞获得不受控制地增殖、抵抗凋亡、维持血管生成和逃避免疫监视的能力。信号转导子和转录激活子（STAT）3在数量惊人的人类癌症中调节所有这些过程。因此，STAT3蛋白正在成为癌症治疗的理想靶点。本文报道了一种溶瘤腺病毒（M4）的产生，它选择性地阻断肿瘤细胞中的STAT3信号转导，作为一种新的治疗策略。M4在肿瘤细胞中选择性复制，并在病毒感染的晚期以复制依赖性方式表达高水平的反义STAT3互补DNA。M4在肿瘤细胞中的病毒子代产量远高于亲本腺病毒突变体Ad5/dE1A。M4有效地沉默了肿瘤细胞中的STAT3及其靶基因，同时保留了正常细胞，并在体外和体内表现出强大的抗肿瘤功效。M4全身给药可显著抑制原位胃癌小鼠模型中的肿瘤生长，消除腹腔转移并延长生存时间。总之，M4具有低毒性和作为不同类型癌症的治疗剂的巨大潜力。
Tumor cells acquire the ability to proliferate uncontrollably, resist apoptosis, sustain angiogenesis and evade immune surveillance. Signal transducer and activator of transcription (STAT) 3 regulates all of these processes in a surprisingly large number of human cancers. Consequently, the STAT3 protein is emerging as an ideal target for cancer therapy. This paper reports the generation of an oncolytic adenovirus (M4), which selectively blocks STAT3 signaling in tumor cells as a novel therapeutic strategy. M4 selectively replicated in tumor cells and expressed high levels of antisense STAT3 complementary DNA during the late phase of the viral infection in a replication-dependent manner. The viral progeny yield of M4 in tumor cells was much higher than that of the parent adenoviral mutants, Ad5/dE1A. M4 effectively silenced STAT3 and its target genes in tumor cells while sparing normal cells and exhibited potent antitumoral efficacy in vitro and in vivo. Systemic administration of M4 significantly inhibited tumor growth in an orthotopic gastric carcinoma mouse model, eliminated abdominal cavity metastases and prolonged survival time. In summary, M4 has low toxicity and great potential as a therapeutic agent for different types of cancers.