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Oncolytic adenovirus-mediated short hairpin RNA targeting MYCN gene induces apoptosis by upregulating RKIP in neuroblastoma

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Tumor Biology

Abstract

The amplification of MYCN is a typical characteristic of aggressive neuroblastomas, whereas acquired mutations of p53 lead to refractory and relapsed cases. We had previously examined the applicability of the replication-competent oncolytic adenovirus, ZD55-shMYCN, to deliver a short hairpin RNA targeting MYCN gene for p53-null and MYCN-amplified neuroblastoma cell line LA1-55N. Our data have shown that ZD55-shMYCN has an additive tumor growth inhibitory response through shRNA-mediated MYCN knockdown and ZD55-mediated cancer cell lysis. In this regard, ZD55-shMYCN can downregulate MYCN and perform anticancer effects, thereby acquiring significance in the administration of MYCN-amplified and p53-null neuroblastomas. Hence, we further investigated the anticancer properties of ZD55-shMYCN in neuroblastomas. Our data showed that ZD55-shMYCN induced G2/M arrest via decreasing the levels of cyclin D1 and cyclin B1 irrespective of p53 status. ZD55-shMYCN effectively induced apoptosis in neuroblastomas through activation of caspase-3 and enhancing PARP cleavage. Furthermore, ZD55-shMYCN could downregulate phosphoinositide 3-kinase and pAkt and upregulate RKIP levels. Similarly, pro-apoptosis was revealed by the histopathologic examination of paraffin-embedded section of resected tumors of mice xenograft. In vitro and in vivo studies, we elucidate the apoptosis properties and mechanisms of action of ZD55-shMYCN, which provide a promising approach for further clinical development.

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Authors and Affiliations

  1. Department of Pediatric Surgery, Xuzhou Children’s Hospital, 18 Suti North Road, Xuzhou, 221006, Jiangsu, China

    Yuan Li, Hongwei Zhang, Xiaoyu Zhu, Dongchuan Feng, Deyong Zhang & Baobiao Zhuo

  2. Laboratory of Biological Cancer Therapy, Xuzhou Medical College, 84 Huaihai West Road, Xuzhou, 221002, Jiangsu, China

    Junnian Zheng

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  1. Yuan Li
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  2. Hongwei Zhang
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  3. Xiaoyu Zhu
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  4. Dongchuan Feng
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Correspondence to Yuan Li or Junnian Zheng.

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Li, Y., Zhang, H., Zhu, X. et al. Oncolytic adenovirus-mediated short hairpin RNA targeting MYCN gene induces apoptosis by upregulating RKIP in neuroblastoma. Tumor Biol. 36, 6037–6043 (2015). https://doi.org/10.1007/s13277-015-3280-y

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  • DOI: https://doi.org/10.1007/s13277-015-3280-y

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