A novel role mediated by adenoviral E1A in suppressing cancer through modulating decorin
A novel role mediated by adenoviral E1A in suppressing cancer through modulating decorin
复制标题
腺病毒 E1A 通过调节核心蛋白聚糖介导抑制癌症的新作用
DOI：
10.1007/s12032-019-1325-6
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发表时间：
2019-12-01
期刊：
影响因子：
3.4
通讯作者：
Zheng，Junnian
中科院分区：
文献类型：
--
作者：
Ge，Yan;Zhang，Wen;Zheng，Junnian
溶瘤腺病毒是一种新兴的替代目前的治疗方法。腺病毒E1 A是溶瘤腺病毒感染后表达的第一个蛋白质，已被鉴定为抗肿瘤剂，但其肿瘤抑制能力的机制尚不清楚。核心蛋白聚糖广泛存在于细胞外基质（ECM）中，通过与ECM相互作用调节多种功能。本研究旨在探讨腺病毒E1 A在基因治疗过程中对肿瘤细胞外基质的影响。我们证明了在肺癌患者中发现核心蛋白聚糖表达减少。腺病毒E1 A或缺失Rb结合能力的突变型腺病毒E1 A（E1 A30 - 60 aa，120- 127 aa缺失）可增加decorin的表达，并下调VEGF（肿瘤ECM的两个成员，参与血管生成和血管生成）的表达。E1 A/mE 1A介导的对肿瘤细胞迁移和侵袭能力的抑制作用依赖于核心蛋白聚糖。E1 A与核心蛋白聚糖直接相互作用，诱导VEGF的蛋白酶体降解。此外，E1 A或mE 1A可以抑制皮下肺癌异种移植模型中的肿瘤生长。这表明核心蛋白聚糖可能是腺病毒E1 A介导的抗肿瘤活性的ECM组分中的重要介质。腺病毒E1 A的研究为肿瘤基因治疗提供了新的机制。
Oncolytic adenovirus is an emerging alternative to current therapeutics. The adenoviral E1A, the first protein expressed upon oncolytic adenoviral infection, has been identified as an antitumor agent, but the mechanisms of its tumor inhibition ability are unclear enough. Decorin is ubiquitous in the extracellular matrix (ECM), which regulates multiple functions through interaction with ECM. Here, we intended to explore the effects of adenoviral E1A on the tumor extracellular matrix during gene therapy. We demonstrated that reduced decorin expression was found in patients with lung cancer. The adenoviral E1A or a mutant adenoviral E1A with Rb-binding ability absent (E1A 30–60aa, 120–127aa deletion) could increase the expression of decorin and down-regulate VEGF, two members of tumor ECM, involved in both vasculogenesis and angiogenesis. E1A/mE1A-mediated suppressing the migration and invasion ability of tumor cells was depended on decorin. E1A interacted with decorin directly and induced the proteasomal degradation of VEGF. In addition, E1A or mE1A can inhibit tumor growth in a subcutaneous lung cancer xenograft model. It suggested that decorin might be a crucial mediator among ECM components for adenoviral E1A-mediated antitumor activities. These studies on adenovirus E1A provide a new mechanism for the emerging therapies of tumor gene therapy.