Small RNA zippers lock miRNA molecules and block miRNA function in mammalian cells

Lingyu Meng; Cuicui Liu; Jinhui Lü; Qian Zhao; Shengqiong Deng; Guangxue Wang; Jing Qiao; Chuyi Zhang; Lixiao Zhen; Ying Lu; Wenshu Li; Yuzhen Zhang; Richard G. Pestell; Huiming Fan; Yi Han Chen; Zhongmin Liu; Zuoren Yu

doi:10.1038/ncomms13964

Small RNA zippers lock miRNA molecules and block miRNA function in mammalian cells

Lingyu Meng, Cuicui Liu, Jinhui Lü, Qian Zhao, Shengqiong Deng, Guangxue Wang, Jing Qiao, Chuyi Zhang, Lixiao Zhen, Ying Lu, Wenshu Li, Yuzhen Zhang, Richard G. Pestell, Huiming Fan, Yi Han Chen, Zhongmin Liu, Zuoren Yu

Research output: Contribution to journal › Article › peer-review

49 Citations (Scopus)

Abstract

MicroRNAs (miRNAs) loss-of-function phenotypes are mainly induced by chemically modified antisense oligonucleotides. Here we develop an alternative inhibitor for miRNAs, termed 'small RNA zipper'. It is designed to connect miRNA molecules end to end, forming a DNA-RNA duplex through a complementary interaction with high affinity, high specificity and high stability. Two miRNAs, miR-221 and miR-17, are tested in human breast cancer cell lines, demonstrating the 70~90% knockdown of miRNA levels by 30-50 nM small RNA zippers. The miR-221 zipper shows capability in rescuing the expression of target genes of miR-221 and reversing the oncogenic function of miR-221 in breast cancer cells. In addition, we demonstrate that the miR-221 zipper attenuates doxorubicin resistance with higher efficiency than anti-miR-221 in human breast cancer cells. Taken together, small RNA zippers are a miRNA inhibitor, which can be used to induce miRNA loss-of-function phenotypes and validate miRNA target genes.

Original language	English
Article number	13964
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms13964
Publication status	Published - 3 Jan 2017
Externally published	Yes

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@article{5c4af5b3af8844a8ab72fdfebf0f3dae,

title = "Small RNA zippers lock miRNA molecules and block miRNA function in mammalian cells",

abstract = "MicroRNAs (miRNAs) loss-of-function phenotypes are mainly induced by chemically modified antisense oligonucleotides. Here we develop an alternative inhibitor for miRNAs, termed 'small RNA zipper'. It is designed to connect miRNA molecules end to end, forming a DNA-RNA duplex through a complementary interaction with high affinity, high specificity and high stability. Two miRNAs, miR-221 and miR-17, are tested in human breast cancer cell lines, demonstrating the 70~90% knockdown of miRNA levels by 30-50 nM small RNA zippers. The miR-221 zipper shows capability in rescuing the expression of target genes of miR-221 and reversing the oncogenic function of miR-221 in breast cancer cells. In addition, we demonstrate that the miR-221 zipper attenuates doxorubicin resistance with higher efficiency than anti-miR-221 in human breast cancer cells. Taken together, small RNA zippers are a miRNA inhibitor, which can be used to induce miRNA loss-of-function phenotypes and validate miRNA target genes.",

author = "Lingyu Meng and Cuicui Liu and Jinhui L{\"u} and Qian Zhao and Shengqiong Deng and Guangxue Wang and Jing Qiao and Chuyi Zhang and Lixiao Zhen and Ying Lu and Wenshu Li and Yuzhen Zhang and Pestell, {Richard G.} and Huiming Fan and Chen, {Yi Han} and Zhongmin Liu and Zuoren Yu",

note = "Funding Information: This work was supported by the National Key Research and Development Program of China Stem Cell and Translational Research (2016YFA0101202); Natural Science Foundation of China (Grant 81572593); partly by grants 13JC1401702 and 124119a7100 from Science and Technology Commission of Shanghai Municipality; partly by NIH grants R01CA070896, R01CA075503, R01CA132115, R01CA107382 and, R01CA086072 (R.G.P.); generous grants from the Dr Ralph and Marian C. Falk Medical Research Trust (R.G.P.); and a grant from Pennsylvania Department of Health (R.G.P.). We thank Dr Reuven Agami for providing WT and mutated pGL3-p27 30-UTR vector. We thank Dr Brian Tomlinson for providing English editing. Publisher Copyright: {\textcopyright} The Author(s) 2017.",

year = "2017",

month = jan,

day = "3",

doi = "10.1038/ncomms13964",

language = "English",

volume = "8",

journal = "Nature Communications",

issn = "2041-1723",

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TY - JOUR

T1 - Small RNA zippers lock miRNA molecules and block miRNA function in mammalian cells

AU - Meng, Lingyu

AU - Liu, Cuicui

AU - Lü, Jinhui

AU - Zhao, Qian

AU - Deng, Shengqiong

AU - Wang, Guangxue

AU - Qiao, Jing

AU - Zhang, Chuyi

AU - Zhen, Lixiao

AU - Lu, Ying

AU - Li, Wenshu

AU - Zhang, Yuzhen

AU - Pestell, Richard G.

AU - Fan, Huiming

AU - Chen, Yi Han

AU - Liu, Zhongmin

AU - Yu, Zuoren

N1 - Funding Information: This work was supported by the National Key Research and Development Program of China Stem Cell and Translational Research (2016YFA0101202); Natural Science Foundation of China (Grant 81572593); partly by grants 13JC1401702 and 124119a7100 from Science and Technology Commission of Shanghai Municipality; partly by NIH grants R01CA070896, R01CA075503, R01CA132115, R01CA107382 and, R01CA086072 (R.G.P.); generous grants from the Dr Ralph and Marian C. Falk Medical Research Trust (R.G.P.); and a grant from Pennsylvania Department of Health (R.G.P.). We thank Dr Reuven Agami for providing WT and mutated pGL3-p27 30-UTR vector. We thank Dr Brian Tomlinson for providing English editing. Publisher Copyright: © The Author(s) 2017.

PY - 2017/1/3

Y1 - 2017/1/3

N2 - MicroRNAs (miRNAs) loss-of-function phenotypes are mainly induced by chemically modified antisense oligonucleotides. Here we develop an alternative inhibitor for miRNAs, termed 'small RNA zipper'. It is designed to connect miRNA molecules end to end, forming a DNA-RNA duplex through a complementary interaction with high affinity, high specificity and high stability. Two miRNAs, miR-221 and miR-17, are tested in human breast cancer cell lines, demonstrating the 70~90% knockdown of miRNA levels by 30-50 nM small RNA zippers. The miR-221 zipper shows capability in rescuing the expression of target genes of miR-221 and reversing the oncogenic function of miR-221 in breast cancer cells. In addition, we demonstrate that the miR-221 zipper attenuates doxorubicin resistance with higher efficiency than anti-miR-221 in human breast cancer cells. Taken together, small RNA zippers are a miRNA inhibitor, which can be used to induce miRNA loss-of-function phenotypes and validate miRNA target genes.

AB - MicroRNAs (miRNAs) loss-of-function phenotypes are mainly induced by chemically modified antisense oligonucleotides. Here we develop an alternative inhibitor for miRNAs, termed 'small RNA zipper'. It is designed to connect miRNA molecules end to end, forming a DNA-RNA duplex through a complementary interaction with high affinity, high specificity and high stability. Two miRNAs, miR-221 and miR-17, are tested in human breast cancer cell lines, demonstrating the 70~90% knockdown of miRNA levels by 30-50 nM small RNA zippers. The miR-221 zipper shows capability in rescuing the expression of target genes of miR-221 and reversing the oncogenic function of miR-221 in breast cancer cells. In addition, we demonstrate that the miR-221 zipper attenuates doxorubicin resistance with higher efficiency than anti-miR-221 in human breast cancer cells. Taken together, small RNA zippers are a miRNA inhibitor, which can be used to induce miRNA loss-of-function phenotypes and validate miRNA target genes.

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U2 - 10.1038/ncomms13964

DO - 10.1038/ncomms13964

M3 - Article

C2 - 28045030

AN - SCOPUS:85008339331

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 13964

ER -

Small RNA zippers lock miRNA molecules and block miRNA function in mammalian cells

Abstract

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