Computational methods for analysis of cellular functions and pathways collectively targeted by differentially expressed microRNA
Methods. 2008 Jan;44(1):61-72
Computational analysis of biological functions and pathways collectively targeted by co-expressed microRNAs in cancer
BMC Bioinformatics. 2007 Nov 1;8 Suppl 7:S16
Two recent articles published by researchers in the Department of Surgery at the University of Oklahoma Health Sciences Center outline a strategy for addressing the data interpretation challenges faced by researchers assaying microRNAs (miRNAs) aberrantly expressed in common human cancers. Advances in methods for understanding the microRNAome – including microarrays, RTPCR, and microbeads – have resulted in the subsequent downstream challenge of interpreting the regulatory impact of these miRNAs. To directly address this challenge, the OUHSC team has outlined a method for prioritizing lists of miRNA targets and performing a detailed analysis of the biological functions, diseases processes, toxicological responses, signaling and metabolic pathways, and drugs most significantly associated with those miRNA targets. By using Ingenuity Pathways Analysis (IPA) to perform an in-depth analysis of genes targeted by miRNA aberrantly expressed in cancer (pancreatic, breast, colon, lung, and lymphoma), the research team established functional links between cancer-related processes and miRNA expression, identified miRNA targets that are known tissue-specific biomarkers of cancer, and narrowed in on pathways specifically to each type of cancer that were enriched for miRNA targets, providing a clear path for follow up experiments.
Because most miRNAs are predicted to target a large number of transcripts, and because tens to hundreds of miRNAs have been found to be aberrantly expressed in human cancers, the predicted number of target genes potentially regulated by these miRNAs can quickly scale to hundreds or thousands of genes. In order to place these large lists of predicted target genes in the context of the larger system being studied – the human cancer cell – the OUHSC team established computational methods for identifying common biological pathways, processes, and themes significantly associated with these sets of target genes. Analysis in IPA specifically provided the team with detailed functional links to cancer related processes such as the cell cycle, cell death, DNA replication, recombination and repair, toxicological processes such as hypoxia, and signaling pathways involving the p38 MAPK superfamily, that are collectively targeted by miRNAs co-expressed in cancer cells. They also used IPA’s extensive chemical and drug searching capabilities to determine that many FDA-approved and clinical candidate anti-cancer compounds target the same cancer-related genes that were predicted to be targeted by miRNAs co-expressed in cancer.
By combining a novel method for prioritizing miRNA target genes with a detailed functional analysis of those lists of target genes in IPA, the authors have provided a viable strategy for quickly interpreting the regulatory impact of miRNAs in cancer cells, and for improving decision making on appropriate next steps to take in their research.
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