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

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 6

Therapeutic effects of edited miR-379-5p in vivo.

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Therapeutic effects of edited miR-379-5p in vivo. (A) Flowchart of in vi...
(A) Flowchart of in vivo experiments. The MDA-MB-231 cell line was used in the xenograft model. MiRNA mimics incorporated into DOPC nanoliposomes were injected as treatment twice a week. Tumor sizes were measured every 3 days using a caliper, and a luciferase picture was taken once a week. (B) In Vivo Imaging Systems images of the mice at the first and fifth weeks. (C) Box plots of tumor sizes measured by caliper of MDA-MB-231 in vivo model at week 4.5; t test was used to assess the statistical difference. The middle line in the box is the mean, 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) Kaplan-Meier survival curves for different mouse groups of MDA-MB-231 in vivo model; P values based on log-rank tests. (E) Tumor sizes (mean with SEM) measured by caliper of A549 in vivo model. A 2-way ANOVA test was used to evaluate the impact of time and different treatments. Each measurement was considered independent, and treatment P value was reported.