The Optimal Outcome of Suppressing Ewing Sarcoma Growth in vivo With Biocompatible Bioengineered miR-34a-5p Prodrug

Dai Feng Li, Ying Yuan, Mei Juan Tu, Xiang Hu, Yi Zhou Li, Wan Rong Yi, Peng Cheng Li, Yong Zhao, Zhen Cheng, Ai Ming Yu, Chao Jian, Ai Xi Yu

Research output: Contribution to journalArticle

Abstract

Being the second most common type of primary bone malignancy in children and adolescents, Ewing Sarcoma (ES) encounters the dilemma of low survival rate with a lack of effective treatments. As an emerging approach to combat cancer, RNA therapeutics may expand the range of druggable targets. Since the genome-derived oncolytic microRNA-34a (miR-34a) is down-regulated in ES, restoration of miR-34a-5p expression or function represents a new therapeutic strategy which is, however, limited to the use of chemically-engineered miRNA mimics. Very recently we have developed a novel bioengineering technology using a stable non-coding RNA carrier (nCAR) to achieve high-yield production of biocompatible miRNA prodrugs, which is a great addition to current tools for the assessment of RNA therapeutics. Herein, for the first time, we investigated the biochemical pharmacology of bioengineered miR-34a-5p prodrug (nCAR/miR-34a-5p) in the control of ES using human ES cells and xenograft mouse models. The bioengineered nCAR/miR-34a-5p was precisely processed to mature miR-34a-5p in ES cells and subsequently suppressed cell proliferation, attributable to the enhancement of apoptosis and induction of G2 cell cycle arrest through downregulation of SIRT-1, BCL-2 and CDK6 protein levels. Furthermore, systemic administration of nCAR/miR-34a-5p dramatically suppressed the ES xenograft tumor growth in vivo while showing biocompatibility. In addition, the antitumor effect of bioengineered nCAR/miR-34a-5p was associated with a lower degree of tumoral cell proliferation and greater extent of apoptosis. These findings demonstrate the efficacy of bioengineered miR-34a-5p prodrug for the treatment of ES and support the development of miRNA therapeutics using biocompatible bioengineered miRNA prodrugs.

Original languageEnglish (US)
Article number222
JournalFrontiers in Oncology
Volume10
DOIs
StatePublished - Feb 25 2020

Keywords

  • apoptosis
  • bioengineered
  • Ewing Sarcoma
  • miR-34a
  • mouse model
  • RNA therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Li, D. F., Yuan, Y., Tu, M. J., Hu, X., Li, Y. Z., Yi, W. R., Li, P. C., Zhao, Y., Cheng, Z., Yu, A. M., Jian, C., & Yu, A. X. (2020). The Optimal Outcome of Suppressing Ewing Sarcoma Growth in vivo With Biocompatible Bioengineered miR-34a-5p Prodrug. Frontiers in Oncology, 10, [222]. https://doi.org/10.3389/fonc.2020.00222