OncoTargets and Therapy (Nov 2017)

Simultaneous overexpression of miR-126 and miR-34a induces a superior antitumor efficacy in pancreatic adenocarcinoma

  • Feng SD,
  • Mao ZM,
  • Liu CY,
  • Nie YS,
  • Sun B,
  • Guo MG,
  • Su CQ

Journal volume & issue
Vol. Volume 10
pp. 5591 – 5604

Abstract

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Shu-De Feng,1,* Ziming Mao,2,* Chunying Liu,2,* Yu-Song Nie,1 Bin Sun,2 Minggao Guo,3 Changqing Su2 1Department of General Surgery, Jiangsu Armed Police General Hospital, Yangzhou, Jiangsu, China; 2Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital, National Center of Liver Cancer, Second Military Medical University, Shanghai, China; 3Department of General Surgery, Shanghai Sixth People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China *These authors contributed equally to this work Background: Pancreatic adenocarcinoma (PAC) is one of the most fatal cancers due to its high degree of malignancy, increasing incidence, high mortality, and unsatisfactory treatment efficacy. Evidence has suggested that numerous microRNAs (miRNAs), including miR-126 and miR-34a, have potent tumor-suppressing effects on PAC, implicating a possible application of miRNA in tumor therapy. However, the therapeutic effect of a single miRNA on pancreatic cancer is limited.Methods: We simultaneously delivered miR-126 and miR-34a into PAC cells by a carcinoem­bryonic antigen promoter-driven oncolytic adenovirus (AdCEAp-miR126/34a), and examined the antitumor efficacy of the therapeutic system in in vitro and in vivo experiments.Results: In vitro cytological experiments found that the expression levels of miR-126 and miR-34a were specifically increased in the AdCEAp-miR126/34a-infected PAC cells, and the antitumor efficacy was enhanced in aspects of cancer cell viability, migration, invasion, and apoptosis, by synergistically combining the antitumor effects of overexpressed miR-126 and miR-34a and the oncolytic effect of viral replication specifically in PAC cells. The expression levels of miR-126 target genes (vascular endothelial growth factor-A and SOX2) and miR-34a target genes (cyclin D1, E2F1, and Bcl-2) were markedly decreased in the PAC cells after being infected with AdCEAp-miR126/34a. Notable suppression of the therapeutic system on tumor growth was also proven in established PAC xenograft tumor models in nude mice, which demonstrated that the combination of miR-126 and miR-34a exerts more effective antitumor outcomes than a single miRNA.Conclusion: The therapeutic system co-expressing miR-126 and miR-34a mediated by oncolytic adenovirus is a promising system for PAC target therapy. Keywords: pancreatic cancer, miR-126, miR-34a, oncolytic adenovirus, target therapy

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