Synthetic circular multi-miR sponge simultaneously inhibits miR-21 and miR-93 in esophageal carcinoma

Zhe Wang, Ke Ma, Yulan Cheng, John M. Abraham, Xi Liu, Xiquan Ke, Zhirong Wang, Stephen J. Meltzer

Research output: Contribution to journalArticle

Abstract

MicroRNAs (miRs) are post-transcriptional regulators involved in the initiation and progression of many tumors. Recently, naturally occurring circular RNAs (circRNAs) have been described in eukaryotic cells:;they comprise a new class of gene regulators. Naturally occurring circular miR sponges, which induce miR loss-of-function, can prevent endogenous onco-miRs from binding to their cognate mRNA targets. These findings suggest that synthetic (artificial) circular RNAs could be constructed as therapeutic molecular sponges to suppress harmful onco-miRs. Using enzymatic ligation, we designed and constructed a circular RNA containing both miR-21 and miR-93 binding sites. The synthetic circular sponge was resistant to digestion with RNase R. Luciferase assays and functional experiments showed that the circular multi-miR sponge was more stable than its linear counterpart. Moreover, endogenous miR-21 and miR-93 were inhibited by the circular sponge. In addition, the synthetic sponge significantly suppressed cellular proliferation and migration while promoting apoptosis in esophageal carcinoma cells. Finally, in a murine xenograft model, the circular sponge significantly inhibited tumor growth in vivo. Taken together, these findings establish that the design and construction of efficient artificial miR sponges represent a novel strategy to achieve miR loss-of-function in molecular cancer therapeutics.

Original languageEnglish (US)
Pages (from-to)1442-1453
Number of pages12
JournalLaboratory Investigation
Volume99
Issue number10
DOIs
StatePublished - Oct 1 2019

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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