Efficacy of an oncolytic adenovirus driven by a chimeric promoter and armed with Decorin against renal cell carcinoma.
Efficacy of an oncolytic adenovirus driven by a chimeric promoter and armed with Decorin against renal cell carcinoma.
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DOI：
10.1089/hum.2019.352
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发表时间：
2020-03
影响因子：
4.2
通讯作者：
Wen Zhang;Chen Zhang;Weiping Tian;Jing Qin;J. Chen;Qi Zhang;Lin Fang;Junnian Zheng
中科院分区：
文献类型：
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作者：
Wen Zhang;Chen Zhang;Weiping Tian;Jing Qin;J. Chen;Qi Zhang;Lin Fang;Junnian Zheng
肿瘤的病毒靶向治疗可以有效延长患者的生存率，已成为肿瘤生物治疗的新趋势。溶瘤腺病毒（OAd）可以在肿瘤细胞中特异性复制，使携带的治疗基因得以快速复制。众所周知，实体瘤总是处于缺氧状态，研究人员往往忽略了一个关键点，溶瘤腺病毒的复制不仅取决于其自身的活性，还取决于病毒复制所处的细胞缺氧环境。在此，我们构建了携带Decorin的溶瘤腺病毒HRE-Ki 67-Decorin，其将Ki 67启动子与缺氧反应元件（HRE）序列上游结合以驱动腺病毒E1 A。溶瘤腺病毒HRE-Ki 67-Decorin在低氧条件下具有更好的复制能力，下调细胞免疫抑制生长因子TGF-β。此外，HRE-Ki 67-Decorin在抑制肿瘤生长方面是有效的，并且通过在皮下肾癌细胞肿瘤模型中表达Decorin而参与肿瘤细胞外基质（ECM）的组装。来自HRE-Ki 67-核心蛋白聚糖处理组织的肿瘤切片的胶原纤维较少，肿瘤组织中的病毒传播较多。这些结果表明，嵌合HRE-Ki 67启动子调控的OAd携带Decorin可能是一种有效的抗肿瘤治疗策略。
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 oncolytic adenovirus depends not only on its own activity but also on the cellular hypoxic environment in which the virus replicates. Here we constructed an oncolytic adenovirus carrying Decorin, HRE-Ki67-Decorin, combining the Ki67 promoter up-streamed with hypoxia response element (HRE) sequences to drive adenoviral E1A. The oncolytic adenovirus HRE-Ki67-Decorin had better replication ability under hypoxic conditions, down-regulated 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 (ECM) by expressing Decorin in subcutaneous renal cancer cells 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 anti-cancer treatment strategy.