Tumor-specific, hypoxia-regulated, WW domain-containing oxidoreductase-expressing adenovirus inhibits human non-small cell lung cancer growth in vivo.
Tumor-specific, hypoxia-regulated, WW domain-containing oxidoreductase-expressing adenovirus inhibits human non-small cell lung cancer growth in vivo.
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DOI：
10.1089/hum.2009.021
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发表时间：
2010
影响因子：
4.2
通讯作者：
Ping Zhang;Lei Ying;Rang Xu;S. Ge;Wenhan Mei;Feng Li;B. Dai;Jian Lu;Guanxiang Qian
中科院分区：
文献类型：
--
作者：
Ping Zhang;Lei Ying;Rang Xu;S. Ge;Wenhan Mei;Feng Li;B. Dai;Jian Lu;Guanxiang Qian
缺氧诱导因子-1(HIF-1)水平升高在实体瘤中很常见，且与预后不良相关。因此，靶向HIF-1为肿瘤治疗提供了一条诱人的途径。在这项研究中，我们在人工合成的人重组端粒酶逆转录酶启动子(HrTRTP)的控制下，构建了携带人WW结构域的氧化还原酶(HWWOX)和HIF-1α氧依赖降解结构域(ODD)的融合的腺病毒载体。荧光素酶报告实验显示，合成的hrTRTP启动子活性在被测试的肿瘤细胞系中升高，但在未转化的细胞系WI-38中没有。此外，腺病毒hrTRTP-hWWOX-Linker-ODD(Ad-TWLH)在低氧条件下诱导多种人癌细胞株的凋亡，并呈剂量依赖关系。重要的是，将Ad-TWLH注射到A549肿瘤细胞的异种移植瘤中，在体内显著减小了肿瘤的大小。Western印迹和免疫组织化学检测也证实hWWOX-Linker-ODD融合蛋白在A549移植瘤中有表达。中心区的蛋白质水平明显高于周边区。综上所述，我们的双调节腺病毒在体外能特异性地诱导低氧条件下人癌细胞的凋亡，并抑制体内异位移植瘤的生长，从而为低氧靶向肿瘤的基因治疗提供了一种新的策略。
An elevated level of hypoxia-inducible factor 1 (HIF-1) is common in solid tumors and correlates with poor prognosis. Therefore, targeting of HIF-1 presents an appealing approach for cancer therapy. In this study, we developed an adenoviral vector carrying a fusion of human WW domain-containing oxidoreductase (hWWOX) and the HIF-1alpha oxygen-dependent degradation domain (ODD) under the control of a synthetic human recombinant telomerase reverse transcriptase promoter (hrTRTP). Luciferase reporter assay showed elevated promoter activity of the synthetic hrTRTP in tested tumor cell lines, but not in WI-38, a nontransformed cell line. Furthermore, adenoviral hrTRTP-hWWOX-Linker-ODD (Ad-TWLH) expression induced apoptosis in a variety of human cancer cell lines under hypoxic conditions dose dependently. Importantly, Ad-TWLH injection into xenografts of A549 tumor cells dramatically reduced tumor size in vivo. Western blot and immunohistochemistry assays also confirmed that hWWOX-Linker-ODD fusion protein was expressed in the A549 xenografts. And the protein level in center part was much higher than that of the circumjacent area. In conclusion, our dual-regulated adenovirus specifically induced apoptosis in human cancer cell lines under hypoxic conditions in vitro and repressed ectopic xenograft tumor growth in vivo, thus providing a novel strategy for hypoxia-targeted cancer gene therapy.