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RNA. 2015 Jun;21(6):1055-65. doi: 10.1261/rna.048132.114. Epub 2015 Apr 7.

Concordant dysregulation of miR-5p and miR-3p arms of the same precursor microRNA may be a mechanism in inducing cell proliferation and tumorigenesis: a lung cancer study.

Author information

1
Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA.
2
Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
3
Machine Intelligence Unit, Indian Statistical Institute, Kolkata 700108, India.
4
Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee 37212, USA Center for Quantitative Sciences, Vanderbilt University, Nashville, Tennessee 37232, USA.

Abstract

A precursor microRNA (miRNA) has two arms: miR-5p and miR-3p (miR-5p/-3p). Depending on the tissue or cell types, both arms can become functional. However, little is known about their coregulatory mechanisms during the tumorigenic process. Here, by using the large-scale miRNA expression profiles of five cancer types, we revealed that several of miR-5p/-3p arms were concordantly dysregulated in each cancer. To explore possible coregulatory mechanisms of concordantly dysregulated miR-5p/-3p pairs, we developed a robust computational framework and applied it to lung cancer data. The framework deciphers miR-5p/-3p coregulated protein interaction networks critical to lung cancer development. As a novel part in the method, we uniquely applied the second-order partial correlation to minimize false-positive regulations. Using 279 matched miRNA and mRNA expression profiles extracted from tumor and normal lung tissue samples, we identified 17 aberrantly expressed miR-5p/-3p pairs that potentially modulate the gene expression of 35 protein complexes. Functional analyses revealed that these complexes are associated with cancer-related biological processes, suggesting the oncogenic potential of the reported miR-5p/-3p pairs. Specifically, we revealed that the reduced expression of miR-145-5p/-3p pair potentially contributes to elevated expression of genes in the "FOXM1 transcription factor network" pathway, which may consequently lead to uncontrolled cell proliferation. Subsequently, the regulation of miR-145-5p/-3p in the FOXM1signaling pathway was validated by a cohort of 104 matched miRNA and protein (reverse-phase protein array) expression profiles in lung cancer. In summary, our computational framework provides a novel tool to study miR-5p/-3p coregulatory mechanisms in cancer and other diseases.

KEYWORDS:

concordant dysregulation; lung cancer; miR-5p/-3p arms; protein array; protein complex

PMID:
25852169
PMCID:
PMC4436660
DOI:
10.1261/rna.048132.114
[Indexed for MEDLINE]
Free PMC Article

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