Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan, Taiwan.
Department of Nursing, Chung Hwa University of Medical Technology, Tainan, Taiwan.
Gene Ther. 2015 Apr;22(4):305-15. doi: 10.1038/gt.2014.122. Epub 2015 Jan 15.
Most solid tumors undergo hypoxia, leading to rapid cell division, metastasis and expansion of a cell population with hallmarks of cancer stem cells (CSCs). Tumor-selective replication of oncolytic adenoviruses may be hindered by oxygen deprivation in tumors. It is desirable to develop a potent oncolytic adenovirus, retaining its antitumor activity even in a hypoxic environment. We have previously generated an Oct4-dependent oncolytic adenovirus, namely Ad9OC, driven by nine copies of the Oct4 response element (ORE) for specifically killing Oct4-overexpressing bladder tumors. Here, we developed a novel Oct4 and hypoxia dual-regulated oncolytic adenovirus, designated AdLCY, driven by both hypoxia response element (HRE) and ORE. We showed that hypoxia-inducible factor (HIF)-2α and Oct4 were frequently overexpressed in hypoxic bladder cancer cells, and HIF-2α was involved in HRE-dependent and Oct4 transactivation. AdLCY exhibited higher cytolytic activities than Ad9OC against hypoxic bladder cancer cells, while sparing normal cells. AdLCY exerted potent antitumor effects in mice bearing human bladder tumor xenografts and syngeneic bladder tumors. It could target hypoxic CD44- and CD133-positive bladder tumor cells. Therefore, AdLCY may have therapeutic potential for targeting hypoxic bladder tumors and CSCs. As Oct4 is expressed in various cancers, AdLCY may be further explored as a broad-spectrum anticancer agent.
大多数实体瘤都经历缺氧，导致细胞快速分裂、转移，并使具有癌症干细胞（CSC）特征的细胞群体扩张。肿瘤选择性复制溶瘤腺病毒可能会受到肿瘤缺氧的阻碍。开发一种有效的溶瘤腺病毒是可取的，即使在缺氧环境中也能保留其抗肿瘤活性。我们之前生成了一种依赖 Oct4 的溶瘤腺病毒，即 Ad9OC，它由 9 个 Oct4 反应元件（ORE）驱动，专门用于杀死过表达 Oct4 的膀胱癌肿瘤。在这里，我们开发了一种新型的 Oct4 和缺氧双重调控的溶瘤腺病毒，命名为 AdLCY，由缺氧反应元件（HRE）和 ORE 共同驱动。我们表明，缺氧诱导因子（HIF）-2α和 Oct4 在缺氧膀胱癌细胞中经常过表达，并且 HIF-2α 参与 HRE 依赖性和 Oct4 反式激活。与 Ad9OC 相比，AdLCY 对缺氧膀胱癌细胞具有更高的细胞溶解活性，同时对正常细胞的毒性较小。AdLCY 在携带人膀胱癌异种移植瘤和同基因膀胱癌的小鼠中表现出强大的抗肿瘤作用。它可以靶向缺氧的 CD44 和 CD133 阳性膀胱癌细胞。因此，AdLCY 可能具有针对缺氧膀胱癌和 CSC 的治疗潜力。由于 Oct4 在各种癌症中表达，因此可以进一步探索 AdLCY 作为广谱抗癌剂。
