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 J.
N1 - Publisher Copyright:
© 2019, The Author(s), under exclusive licence to United States and Canadian Academy of Pathology.
PY - 2019/10/1
Y1 - 2019/10/1
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.
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U2 - 10.1038/s41374-019-0273-2
DO - 10.1038/s41374-019-0273-2
M3 - Article
C2 - 31217510
AN - SCOPUS:85067873608
SN - 0023-6837
VL - 99
SP - 1442
EP - 1453
JO - Laboratory Investigation
JF - Laboratory Investigation
IS - 10
ER -