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 1

Clinically relevant patterns of miR-379-5p RNA editing in TCGA patient samples.

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Clinically relevant patterns of miR-379-5p RNA editing in TCGA patient s...
(A) Schematic of RNA editing in miR-379-5p, showing the miRNA stem-loop (blue), mature miRNA (orange), seed region (purple), and editing site (red). (B) Expression amount of edited miR-379-5p in the context of WT miRNA expression in various normal tissues. Rank of edited miR-379-5p upper-quantile expression value relative to the median expression of all WT human miRNAs in different cancer types (x axis). Raw expression amount (reads per million mapped reads to miRNA [RPM]) of edited miR-379-5p (y axis). Magnified panels show the background distribution of WT miRNAs in representative cancer types. (C) Editing-level comparison between tumor samples and matched normal samples in the cancer types. Raw P values based on paired Wilcoxon test; statistically significant differences (q < 0.05) are reported. The middle line in the box is the median, the bottom and top of the box are the first and third quartiles, and the whiskers extend to 1.5 times the interquartile range of the lower and the upper quartiles, respectively. (D) Significant survival correlations of miR-379-5p editing level with patient disease-specific survival times in different cancer types (P < 0.05); P values based on Cox proportional hazards models. The groups are separated by median values. (E) Summary of Cox proportional hazard ratio model of miR-379-5p editing level with patient disease-specific survival. Dot size represents level of statistical significance; color indicates correlation direction. Pink blocks highlight P < 0.05. Stage and age as confounding factors are included in the model for comparison.