A-to-I–edited miRNA-379-5p inhibits cancer cell proliferation through CD97-induced apoptosis
Xiaoyan Xu, … , Gordon B. Mills, Han Liang
Xiaoyan Xu, … , Gordon B. Mills, Han Liang
Published December 2, 2019; First published November 4, 2019
Citation Information: J Clin Invest. 2019;129(12):5343-5356. https://doi.org/10.1172/JCI123396.
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Research Article Oncology Therapeutics

A-to-I–edited miRNA-379-5p inhibits cancer cell proliferation through CD97-induced apoptosis

Abstract

Both miRNAs and A-to-I RNA editing, a widespread nucleotide modification mechanism, have recently emerged as key players in cancer pathophysiology. However, the functional impact of RNA editing of miRNAs in cancer remains largely unexplored. Here, we focused on an ADAR2-catalyzed RNA editing site within the miR-379-5p seed region. This site was under-edited in tumors relative to normal tissues, with a high editing level being correlated with better patient survival times across cancer types. We demonstrated that in contrast to wild-type miRNA, edited miR-379-5p inhibited cell proliferation and promoted apoptosis in diverse tumor contexts in vitro, which was due to the ability of edited but not wild-type miR-379-5p to target CD97. Importantly, through nanoliposomal delivery, edited miR-379-5p mimics significantly inhibited tumor growth and extended survival of mice. Our study indicates a role of RNA editing in diversifying miRNA function during cancer progression and highlights the translational potential of edited miRNAs as a new class of cancer therapeutics.

Authors

Xiaoyan Xu, Yumeng Wang, Kamalika Mojumdar, Zhicheng Zhou, Kang Jin Jeong, Lingegowda S. Mangala, Shuangxing Yu, Yiu Huen Tsang, Cristian Rodriguez-Aguayo, Yiling Lu, Gabriel Lopez-Berestein, Anil K. Sood, Gordon B. Mills, Han Liang

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Figure 2

Effects of RNA editing in miR-379-5p on cell proliferation and clone formation.

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Effects of RNA editing in miR-379-5p on cell proliferation and clone for...
(A) Effects of edited miR-379-5p mimics on cell viability in 2D cultured MDA-MB-231, OVCAR-8, 786-O, and A549 cells by IncuCyte proliferation assays. (B and C) Clone formation assays transfected with negative control, WT, and edited miR-379-5p mimics (B), and summary of the clone number (C). (D–G) Representative images of cell viability assays transfected with negative control, WT, and miR-379-5p mimics in 3D cultured cell lines (D); and summary of relative cell viability (E), area (1 outlier, 11.25 in MDA-MB-231 negative control, not shown) (F), and perimeter (2 outliers, 5.88 in MDA-MB-231 negative control and 4.09 in MDA-MB-231 WT, not shown) (G). All data are based on 3 independent experiments. Error bars denote ± SEM; ANOVA followed by Tukey’s test, *P < 0.05; **P < 0.01; ***P < 0.001.