Journal article
Reproducible combinatorial regulatory networks elucidate novel oncogenic microRNAs in non-small cell lung cancer
RNA, Vol.20, pp.1356-1368
2014
Abstract
While previous studies reported aberrant expression of microRNAs (miRNAs) in non-small cell lung cancer (NSCLC), little is known about which miRNAs play central roles in NSCLC's pathogenesis and its regulatory mechanisms. To address this issue, we presented a robust computational framework that integrated matched miRNA and mRNA expression profiles in NSCLC using feed-forward loops. The network consists of miRNAs, transcription factors (TFs), and their common predicted target genes. To discern the biological meaning of their associations, we introduced the direction of regulation. A network edge validation strategy using three independent NSCLC expression profiling data sets pinpointed reproducible biological regulations. Reproducible regulation, which may reflect the true molecular interaction, has not been applied to miRNA-TF co-regulatory network analyses in cancer or other diseases yet. We revealed eight hub miRNAs that connected to a higher proportion of targets validated by independent data sets. Network analyses showed that these miRNAs might have strong oncogenic characteristics. Furthermore, we identified a novel miRNA-TF co-regulatory module that potentially suppresses the tumor suppressor activity of the TGF-β pathway by targeting a core pathway molecule (TGFBR2). Follow-up experiments showed two miRNAs (miR-9-5p and miR-130b-3p) in this module had increased expression while their target gene TGFBR2 had decreased expression in a cohort of human NSCLC. Moreover, we demonstrated these two miRNAs directly bind to the 3′ untranslated region of TGFBR2. This study enhanced our understanding of miRNA-TF co-regulatory mechanisms in NSCLC. The combined bioinformatics and validation approach we described can be applied to study other types of diseases.
Details
- Title
- Reproducible combinatorial regulatory networks elucidate novel oncogenic microRNAs in non-small cell lung cancer
- Authors
- Ramkrishna Mitra (Author) - Vanderbilt University School of Medicine, United StatesMick D Edmonds (Author) - Vanderbilt University School of Medicine, United StatesJingchun Sun (Author) - Vanderbilt University School of Medicine, United StatesMin Zhao (Author) - Vanderbilt University School of Medicine, United StatesHui Yu (Author) - Vanderbilt University School of Medicine, United StatesChristine M Eischen (Author) - Vanderbilt University School of Medicine, United StatesZhongming Zhao (Author) - Vanderbilt University School of Medicine, United States
- Publication details
- RNA, Vol.20, pp.1356-1368
- Publisher
- Cold Spring Harbor Laboratory Press
- Date published
- 2014
- DOI
- 10.1261/rna.042754.113
- ISSN
- 1355-8382
- Copyright note
- Copyright © 2014 Mitra et al. This article is distributed exclusively by the RNA Society for the first 12 months after the full-issue publication date (see http:// rnajournal.cshlp.org/site/misc/terms.xhtml). After 12 months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
- Organisation Unit
- School of Science and Engineering - Legacy; University of the Sunshine Coast, Queensland; School of Science, Technology and Engineering; Centre for Bioinnovation
- Language
- English
- Record Identifier
- 99450547602621
- Output Type
- Journal article
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