Synergistic tumor suppression by adenovirus-mediated ING4/PTEN double gene therapy for gastric cancer
Synergistic tumor suppression by adenovirus-mediated ING4/PTEN double gene therapy for gastric cancer
复制标题
腺病毒介导的ING4/PTEN双基因疗法协同抑制胃癌
DOI：
10.1038/cgt.2015.59
复制
发表时间：
2016
影响因子：
6.4
通讯作者：
Xie Yufeng
中科院分区：
文献类型：
--
作者：
Zhang Haitao;Zhou Xiumin;Xu Chun;Yang Jicheng;Xiang Jim;Tao Min;Xie Yufeng
生长抑制剂4（ING 4）和磷酸酶和张力蛋白同源物（PTEN）都已被证明是强的候选肿瘤抑制剂。然而，ING 4和PTEN对人胃癌的联合疗效仍有待确定。本研究构建了共表达ING 4和PTEN的多启动子表达盒重组腺病毒（AdVING 4/PTEN），并利用野生型p53 AGS和SNU-1人胃癌细胞株研究了AdVING 4/PTEN对胃癌的联合作用，并探讨了其作用机制。我们发现AdVING 4/PTEN在体外AGS或SNU-1肿瘤细胞以及在裸鼠皮下接种的AGS异种移植瘤中诱导协同生长抑制和凋亡。在机制上，AdVING 4/PTEN在体外和体内表现出对p53、Ac-p53（K382）、P21、Bax、Noxa、裂解的Caspase-9、裂解的Caspase-3和裂解的PARP的上调以及Bcl-2的下调的增强作用。此外，AdVING 4/PTEN协同下调肿瘤血管CD 34的表达，降低微血管密度，并在体内叠加抑制血管内皮生长因子（VEGF）的表达。AdVING 4/PTEN协同抑瘤作用与协同诱导凋亡密切相关，可能是通过协同促进p53的稳定性和乙酰化，增强内源性p53反应，协同下调缺氧诱导因子-1 α的水平和转录活性，重叠减少VEGF，协同抑制肿瘤血管生成。因此，我们的研究结果表明，癌症基因治疗结合ING 4和PTEN可能构成一个新的和有效的治疗模式，对人类胃癌和其他癌症。
Both inhibitor of growth 4 (ING4) and phosphatase and tensin homolog (PTEN) have been shown to be strong candidate tumor suppressors. However, the combined efficacy of ING4 and PTEN for human gastric cancer remains to be determined. In this report, we constructed a multiple promoter expression cassette-based recombinant adenovirus coexpressing ING4 and PTEN (AdVING4/PTEN), assessed the combined effects of AdVING4/PTEN on gastric cancer using wild-type p53 AGS and SNU-1 human gastric cancer cell lines, and elucidated its underlying mechanisms. We found that AdVING4/PTEN-induced synergistic growth inhibition and apoptosis in vitro AGS or SNU-1 tumor cells and in vivo AGS xenografted tumors subcutaneously inoculated in athymic BALB/c nude mice. Mechanistically, AdVING4/PTEN exhibited an enhanced effect on upregulation of p53, Ac-p53 (K382), P21, Bax, PUMA, Noxa, cleaved Caspase-9, cleaved Caspase-3 and cleaved PARP as well as downregulation of Bcl-2 in vitro and in vivo. In addition, AdVING4/PTEN synergistically downregulated tumor vessel CD34 expression and reduced microvessel density, and additively inhibited vascular endothelial growth factor (VEGF) expression in vivo. The synergistic tumor suppression elicited by AdVING4/PTEN was closely associated with the synergistic induction of apoptosis possibly via enhancement of endogenous p53 responses through cooperatively facilitating p53’s stability and acetylation, and the synergistic inhibition of tumor angiogenesis probably via overlapping reduction of VEGF through cooperatively downregulating hypoxia inducible factor-1α’s level and transcription activity. Thus, our results indicate that cancer gene therapy combining ING4 and PTEN may constitute a novel and effective therapeutic modality for human gastric cancer and other cancers.