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 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)
JournalLaboratory Investigation
DOIs
StatePublished - Jan 1 2019

Fingerprint

Porifera
Carcinoma
MicroRNAs
Neoplasms
Eukaryotic Cells
Regulator Genes
Luciferases
Heterografts
Ligation
Digestion
Binding Sites
Cell Proliferation
Apoptosis
Messenger RNA
Therapeutics
Growth
circular RNA

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

Cite this

Synthetic circular multi-miR sponge simultaneously inhibits miR-21 and miR-93 in esophageal carcinoma. / Wang, Zhe; Ma, Ke; Cheng, Yulan; Abraham, John M.; Liu, Xi; Ke, Xiquan; Wang, Zhirong; Meltzer, Stephen.

In: Laboratory Investigation, 01.01.2019.

Research output: Contribution to journalArticle

Wang, Zhe ; Ma, Ke ; Cheng, Yulan ; Abraham, John M. ; Liu, Xi ; Ke, Xiquan ; Wang, Zhirong ; Meltzer, Stephen. / Synthetic circular multi-miR sponge simultaneously inhibits miR-21 and miR-93 in esophageal carcinoma. In: Laboratory Investigation. 2019.
@article{04c47fb55eb04cbb90d3a261ab0598ae,
title = "Synthetic circular multi-miR sponge simultaneously inhibits miR-21 and miR-93 in esophageal carcinoma",
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.",
author = "Zhe Wang and Ke Ma and Yulan Cheng and Abraham, {John M.} and Xi Liu and Xiquan Ke and Zhirong Wang and Stephen Meltzer",
year = "2019",
month = "1",
day = "1",
doi = "10.1038/s41374-019-0273-2",
language = "English (US)",
journal = "Laboratory Investigation",
issn = "0023-6837",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Synthetic circular multi-miR sponge simultaneously inhibits miR-21 and miR-93 in esophageal carcinoma

AU - Wang, Zhe

AU - Ma, Ke

AU - Cheng, Yulan

AU - Abraham, John M.

AU - Liu, Xi

AU - Ke, Xiquan

AU - Wang, Zhirong

AU - Meltzer, Stephen

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85067873608&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067873608&partnerID=8YFLogxK

U2 - 10.1038/s41374-019-0273-2

DO - 10.1038/s41374-019-0273-2

M3 - Article

C2 - 31217510

AN - SCOPUS:85067873608

JO - Laboratory Investigation

JF - Laboratory Investigation

SN - 0023-6837

ER -