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 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 4

A-to-I editing in miR-379-5p redirects the target genes in cancer cells.

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A-to-I editing in miR-379-5p redirects the target genes in cancer cells....
(A) Schematic of identification of WT and edited miR-379-5p target genes using mRNA sequencing. Among the target gene candidates, PTK2 is a known target gene for WT miR-379-5p, while CD97 is the top candidate for edited miR-379-5p. Their 3′-UTR sequences with predicted miRNA binding sites are shown. (B) Quantitative reverse transcriptase PCR (RT-qPCR) of PTK2 upon 24-hour transfection with negative control, WT, and edited miR-379-5p mimics in MDA-MB-231, OVCAR-8, 786-O, and A549 cells. (C) Western blots of PTK2 upon 72-hour transfection with negative control, WT, and edited miR-379-5p mimics in the 4 cell lines. (D) RT-qPCR of CD97 upon 24-hour transfection with negative control, WT, and edited miR-379-5p mimics in the 4 cell lines. (E) Western blots of CD97 upon 72-hour transfection with negative control, WT, and edited miR-379-5p mimics in the 4 cell lines. SE, short exposure; LE, long exposure. Cleaved caspase-3 is shown as an apoptosis marker; red arrow indicates the band of interest. (F) Luciferase reporter assays that contain 1 predicted binding site of edited miR-379-5p in CD97 3′-UTR. In B–F, error bars denote mean ± SEM; ANOVA followed by Tukey’s test, **P < 0.01; ***P < 0.001.