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
- Ramkrishna Mitra1,
- Chen-Ching Lin1,
- Christine M. Eischen2,
- Sanghamitra Bandyopadhyay3 and
- Zhongming Zhao1,4,5,6
- 1Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA
- 2Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
- 3Machine Intelligence Unit, Indian Statistical Institute, Kolkata 700108, India
- 4Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
- 5Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee 37212, USA
- 6Center for Quantitative Sciences, Vanderbilt University, Nashville, Tennessee 37232, USA
- Corresponding author: zhongming.zhao{at}vanderbilt.edu
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.
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Article published online ahead of print. Article and publication date are at http://www.rnajournal.org/cgi/doi/10.1261/rna.048132.114.
- Received September 16, 2014.
- Accepted February 11, 2015.
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