title: Coordinate microRNA-mediated regulation of protein complexes in prostate cancer.
abstract: MicroRNAs are a class of small non-coding regulatory RNA molecules that regulate mRNAs post-transcriptionally. Recent evidence has shown that miRNAs target entire functionally related proteins such as protein complexes and biological pathways. However, characterizing the influence of miRNAs on genes whose encoded proteins are part of protein complexes has not been studied in the context of disease. We propose an entropy-based framework to identify miRNA-mediated dysregulation of functionally related proteins during prostate cancer progression. The proposed framework uses experimentally verified miRNA-target interactions, functionally related proteins and expression data to identify miRNA-influenced protein complexes in prostate cancer, and identify genes that are dysregulated as a result. The framework constructs correlation matrixes between functionally related proteins and miRNAs that have targets in the complex, and assesses the changes in the Shannon entropy of the modules across different stages of prostate cancer. Results reveal that SMAD4 and HDAC containing protein complexes are highly affected and disrupted by miRNAs, particularly miRNA-1 and miRNA-16. Using biological pathways to define functionally related proteins reveals that NF-kB-, RAS-, and Syndecan-mediated pathways are dysregulated due to miRNA-1- and miRNA-16-mediated regulation. These results suggest that miRNA-1 and miRNA-16 are important master regulators of miRNA-mediated regulation in prostate cancer. Moreover, results reveal that miRNAs with high-influence on the disrupted protein complexes are diagnostic and prognostic biomarker candidates for prostate cancer progression. The observation of miRNA-mediated protein complex regulation and miRNA-mediated pathway regulation, with partial experimental verification from previous studies, demonstrates that our framework is a promising approach for the identification of novel miRNAs and protein complexes related to disease progression.
authors.affiliation: Department of Computer Science, University of Calgary, Calgary, Alberta, Canada ; Biotechnology Research Centre, Palestine Polytechnic University, Hebron, Palestine.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Alshalalfa
authors.affiliation: The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada and the Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Bader
authors.affiliation: Departments of Pathology, Oncology and Molecular Biology and Biochemistry, Faculty of Medicine, University of Calgary, Alberta, Canada.
authors.forename: Tarek A
authors.initials: TA
authors.lastname: Bismar
authors.affiliation: Department of Computer Science, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Reda
authors.initials: R
authors.lastname: Alhajj
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D019277:Entropy; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics / Q000502:physiology*; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D051901:Smad4 Protein / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C544547:MIRN1 microRNA, human; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; D046912:Multiprotein Complexes; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1