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

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• 作者：Yuan Li ; Hongwei Zhang ; Xiaoyu Zhu ; Dongchuan Feng ; Deyong Zhang…
• 关键词：Neuroblastoma ; Oncolytic adenovirus ; MYCN ; Short hairpin RNA ; Apoptosis
• 刊名：Tumor Biology
• 出版年：2015
• 出版时间：August 2015
• 年：2015
• 卷：36
• 期：8
• 页码：6037-6043
• 全文大小：682 KB
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• 作者单位：Yuan Li (1)
  Hongwei Zhang (1)
  Xiaoyu Zhu (1)
  Dongchuan Feng (1)
  Deyong Zhang (1)
  Baobiao Zhuo (1)
  Junnian Zheng (2)
  
  1. Department of Pediatric Surgery, Xuzhou Children鈥檚 Hospital, 18 Suti North Road, Xuzhou, 221006, Jiangsu, China
  2. Laboratory of Biological Cancer Therapy, Xuzhou Medical College, 84 Huaihai West Road, Xuzhou, 221002, Jiangsu, China
  
• 刊物主题：Cancer Research;
• 出版者：Springer Netherlands
• ISSN：1423-0380

文摘

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. Keywords Neuroblastoma Oncolytic adenovirus MYCN Short hairpin RNA Apoptosis