A novel role mediated by adenoviral E1A in suppressing cancer through modulating decorin
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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.
KeywordsAdenoviral E1A Decorin VEGF Extracellular matrix Lung carcinoma
This project is supported by grants from the National Key Research and Development Plan (2018YFA0900900), the National Natural Science Foundation of China (Grant Nos. 81872488, 81372460), the Natural Science Foundation of Jiangsu Province (Grants Nos. BK20161156, BK20161157), the Education Department of Jiangsu Province (Grant Nos. 13KJB320028, 12KJA320001), Social Development Key Project of Jiangsu Province (Grant Nos. BE2016643), Jiangsu Provincial Medical Youth Talent (Grant Nos. QNRC2016774, QNRC2016773, CXTDA2017034, The Project of Invigorating Health Care through Science, Technology and Education) and Jiangsu Provincial Key Medical Discipline, The Project of Invigorating Health Care through Science, Technology and Education (No. ZDXKA2016014).
Conflicts of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Animal welfare and experimental procedures were carried out strictly in accordance with Guide for the Care and Use of Laboratory Animals (National Research Council, 1996) and all procedures performed in studies involving animals were in accordance with the ethical standards of the Animal Care Committee of the Xuzhou Medical University, Xuzhou, China.
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