Cancer Institute, Xuzhou Medical University, Xuzhou, China; and.
Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
Hum Gene Ther. 2020 Jun;31(11-12):651-663. doi: 10.1089/hum.2019.352. Epub 2020 May 14.
Virus-targeted therapy for tumors can effectively prolong the survival rate of patients and has become a new trend for cancer biotherapy. Oncolytic adenovirus (OAd) can specifically replicate in tumor cells, allowing the therapeutic genes carried to be rapidly copied. As known, solid tumors are always hypoxic, and researchers often overlook a key point, the replication of OAd depends not only on its own activity but also on the cellular hypoxic environment in which the virus replicates. In this study, we constructed an OAd carrying Decorin, HRE-Ki67-Decorin, combining the Ki67 promoter upstreamed with hypoxia-response element (HRE) sequences to drive adenoviral E1A. The OAd HRE-Ki67-Decorin had better replication ability under hypoxic conditions, downregulated cellular immunosuppressed growth factor TGF-β. In addition, HRE-Ki67-Decorin was potent in suppressing tumor growth and participated in the assembly of tumor extracellular matrix by expressing Decorin in subcutaneous renal cancer cell tumor models. Tumor sections from HRE-Ki67-Decorin-treated tissues had less collagen fibers and more spread of virus among tumor tissues. These results indicated that chimeric HRE-Ki67 promoter-regulated OAd carrying Decorin might be an effective anticancer treatment strategy.
肿瘤的病毒靶向治疗可以有效延长患者的生存率，已成为癌症生物治疗的新趋势。溶瘤腺病毒（OAd）可以特异性地在肿瘤细胞中复制，使携带的治疗基因迅速复制。众所周知，实体瘤总是缺氧的，研究人员常常忽略一个关键要点，即 OAd 的复制不仅依赖于自身的活性，还依赖于病毒复制的细胞缺氧环境。在这项研究中，我们构建了携带 Decorin 的 OAd，即 HRE-Ki67-Decorin，将带有缺氧反应元件（HRE）序列的 Ki67 启动子上游与腺病毒 E1A 结合。在缺氧条件下，OAd HRE-Ki67-Decorin 的复制能力更好，下调了细胞免疫抑制生长因子 TGF-β。此外，HRE-Ki67-Decorin 能够有效抑制肿瘤生长，并通过在皮下肾癌肿瘤模型中表达 Decorin 参与肿瘤细胞外基质的组装。来自 HRE-Ki67-Decorin 治疗组织的肿瘤切片显示胶原纤维较少，病毒在肿瘤组织中的扩散更多。这些结果表明，携带 Decorin 的嵌合 HRE-Ki67 启动子调控的 OAd 可能是一种有效的抗癌治疗策略。
