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A Complete Pipeline for Isolating and Sequencing MicroRNAs, and Analyzing Them Using Open Source Tools
Published on: August 21, 2019
Systematic characterization of A-to-I RNA editing hotspots in microRNAs across human cancers
Yumeng Wang1,2, Xiaoyan Xu2,3, Shuangxing Yu4
1Graduate Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
Abstract:
RNA editing, a widespread post-transcriptional mechanism, has emerged as a new player in cancer biology. Recent studies have reported key roles for individual miRNA editing events, but a comprehensive picture of miRNA editing in human cancers remains largely unexplored. Here, we systematically characterized the miRNA editing profiles of 8595 samples across 20 cancer types from miRNA sequencing data of The Cancer Genome Atlas and identified 19 adenosine-to-inosine (A-to-I) RNA editing hotspots. We independently validated 15 of them by perturbation experiments in several cancer cell lines. These miRNA editing events show extensive correlations with key clinical variables (e.g., tumor subtype, disease stage, and patient survival time) and other molecular drivers. Focusing on the RNA editing hotspot in miR-200b, a key tumor metastasis suppressor, we found that the miR-200b editing level correlates with patient prognosis opposite to the pattern observed for the wild-type miR-200b expression. We further experimentally showed that, in contrast to wild-type miRNA, the edited miR-200b can promote cell invasion and migration through its impaired ability to inhibit ZEB1/ZEB2 and acquired concomitant ability to repress new targets, including LIFR, a well-characterized metastasis suppressor. Our study highlights the importance of miRNA editing in gene regulation and suggests its potential as a biomarker for cancer prognosis and therapy.
Insights
RNA editing in microRNAs (miRNAs) is crucial in cancer. This study identified 19 RNA editing hotspots across 20 cancer types, revealing their links to clinical outcomes and metastasis. Edited miR-200b promotes cancer cell invasion.
Area of Science:
- Molecular Biology
- Cancer Research
- Genomics
Background:
- RNA editing is a critical post-transcriptional modification.
- MicroRNA (miRNA) editing's role in cancer is increasingly recognized but not fully understood.
- A comprehensive characterization of miRNA editing across diverse human cancers is lacking.
Purpose of the Study:
- To systematically analyze miRNA editing profiles in human cancers.
- To identify novel RNA editing hotspots and their clinical significance.
- To investigate the functional impact of specific miRNA editing events in cancer progression.
Main Methods:
- Analysis of miRNA sequencing data from The Cancer Genome Atlas (TCGA) for 8595 samples across 20 cancer types.
- Identification and validation of adenosine-to-inosine (A-to-I) RNA editing hotspots.
- Perturbation experiments in cancer cell lines.
- Correlation analysis with clinical variables and molecular drivers.
Main Results:
- Identified 19 adenosine-to-inosine (A-to-I) RNA editing hotspots across 20 cancer types.
- Validated 15 editing events, showing correlations with tumor subtype, stage, and patient survival.
- Demonstrated that edited miR-200b promotes cell invasion by altering target repression, contrasting with wild-type miR-200b function.
Conclusions:
- miRNA editing plays a significant role in human cancer biology.
- Identified miRNA editing hotspots may serve as potential biomarkers for cancer prognosis and therapy.
- Functional studies reveal edited miR-200b's pro-metastatic role, highlighting its distinct regulatory functions compared to the wild-type form.
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