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Molecular Cancer
Published in: Molecular Cancer 1/2016

Open Access 01-12-2016 | Research

Systems analysis identifies miR-29b regulation of invasiveness in melanoma

Authors: Miles C. Andrews, Joseph Cursons, Daniel G. Hurley, Matthew Anaka, Jonathan S. Cebon, Andreas Behren, Edmund J. Crampin

Published in: Molecular Cancer | Issue 1/2016

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Abstract

Background

In many cancers, microRNAs (miRs) contribute to metastatic progression by modulating phenotypic reprogramming processes such as epithelial-mesenchymal plasticity. This can be driven by miRs targeting multiple mRNA transcripts, inducing regulated changes across large sets of genes. The miR-target databases TargetScan and DIANA-microT predict putative relationships by examining sequence complementarity between miRs and mRNAs. However, it remains a challenge to identify which miR-mRNA interactions are active at endogenous expression levels, and of biological consequence.

Methods

We developed a workflow to integrate TargetScan and DIANA-microT predictions into the analysis of data-driven associations calculated from transcript abundance (RNASeq) data, specifically the mutual information and Pearson’s correlation metrics. We use this workflow to identify putative relationships of miR-mediated mRNA repression with strong support from both lines of evidence. Applying this approach systematically to a large, published collection of unique melanoma cell lines – the Ludwig Melbourne melanoma (LM-MEL) cell line panel – we identified putative miR-mRNA interactions that may contribute to invasiveness. This guided the selection of interactions of interest for further in vitro validation studies.

Results

Several miR-mRNA regulatory relationships supported by TargetScan and DIANA-microT demonstrated differential activity across cell lines of varying matrigel invasiveness. Strong negative statistical associations for these putative regulatory relationships were consistent with target mRNA inhibition by the miR, and suggest that differential activity of such miR-mRNA relationships contribute to differences in melanoma invasiveness. Many of these relationships were reflected across the skin cutaneous melanoma TCGA dataset, indicating that these observations also show graded activity across clinical samples. Several of these miRs are implicated in cancer progression (miR-211, -340, -125b, −221, and -29b). The specific role for miR-29b-3p in melanoma has not been well studied. We experimentally validated the predicted miR-29b-3p regulation of LAMC1 and PPIC and LASP1, and show that dysregulation of miR-29b-3p or these mRNA targets can influence cellular invasiveness in vitro.

Conclusions

This analytic strategy provides a comprehensive, systems-level approach to identify miR-mRNA regulation in high-throughput cancer data, identifies novel putative interactions with functional phenotypic relevance, and can be used to direct experimental resources for subsequent experimental validation.
Appendix
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Metadata
Title
Systems analysis identifies miR-29b regulation of invasiveness in melanoma
Authors
Miles C. Andrews
Joseph Cursons
Daniel G. Hurley
Matthew Anaka
Jonathan S. Cebon
Andreas Behren
Edmund J. Crampin
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2016
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-016-0554-y

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CCL18 from ascites promotes ovarian cancer cell migration through proline-rich tyrosine kinase 2 signaling
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

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Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
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