A miRNA-regulatory network explains how dysregulated miRNAs perturb oncogenic processes across diverse cancers

Abstract

Genes regulated by the same miRNA can be discovered by virtue of their coexpression at the transcriptional level and the presence of a conserved miRNA-binding site in their 39 UTRs. Using this principle we have integrated the three best performing and complementary algorithms into a framework for inference of regulation by miRNAs (FIRM) from sets of coexpressed genes. We demonstrate the utility of FIRM by inferring a cancer-miRNA regulatory network through the analysis of 2240 gene coexpression signatures from 46 cancers. By analyzing this network for functional enrichment of known hallmarks of cancer we have discovered a subset of 13 miRNAs that regulate oncogenic processes across diverse cancers. We have performed experiments to test predictions from this miRNA-regulatory network to demonstrate that miRNAs of the miR-29 family (miR-29a, miR-29b, and miR-29c) regulate specific genes associated with tissue invasion and metastasis in lung adenocarcinoma. Further, we highlight the specificity of using FIRM inferences to identify miRNAregulated genes by experimentally validating that miR-767-5p, which partially shares the miR-29 seed sequence, regulates only a subset of miR-29 targets. By providing mechanistic linkage between miRNA dysregulation in cancer, their binding sites in the 39UTRs of specific sets of coexpressed genes, and their associations with known hallmarks of cancer, FIRM, and the inferred cancer miRNA-regulatory network will serve as a powerful public resource for discovery of potential cancer biomarkers.

MiR-155–regulated molecular network orchestrates cell fate in the innate and adaptive immune response to Mycobacterium tuberculosis

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“…5,31 Among other tumor entities, both of these miRNAs are known to be deregulated in nonsmall cell lung cancer. [31][32][33][34][35][36] The role of miRNAs in cancer biology, prognosis prediction, and as a diagnostic tool in non-small cell lung cancer without neuroendocrine features has been intensively studied. 3,5,37 Besides miR-34 and miR-29 family members, let-7a overexpression, possibly through suppression of the RAS oncogene, was shown to be related to increased overall survival in non-small cell lung cancer patients.…”

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