Abstract
BackgroundDespite the lack of agreement on their exact roles, it is known that miRNAs contribute to cancer progression. Many studies utilize methods to detect differential regulation of miRNA expression. It is prohibitively expensive to examine all potentially dysregulated miRNAs and traditionally, researchers have focused their efforts on the most extremely dysregulated miRNAs. These methods may overlook the contribution of less differentially expressed but more functionally relevant miRNAs. The purpose of this study was to outline a method that not only utilizes differential expression but ranks miRNAs based on the functional relevance of their targets. This work uses a networks based approach to determine the sum node degree for all experimentally verified miRNA targets to identify potential regulators of prostate cancer initiation, progression and metastasis.ResultsHere, we present a method for identifying functionally relevant miRNAs that contribute to prostate cancer development. This paper shows that miRNAs preferentially regulate highly connected, central proteins within a protein-protein interaction network. Known targets of miRNAs differentially regulated during prostate cancer progression are enriched in pathways with known involvement in tumorigenesis. To demonstrate the applicability of our method, we utilized a unique model of prostate cancer progression to identify five miRNAs that may contribute to the oncogenic state of the cell. Three of these miRNAs have been shown by other studies to have a role in cancer but their exact role in prostate cancer remains undefined.ConclusionDeveloping methods to determine which miRNAs to carry forward into biological and biochemical analyses is important as traditional approaches often overlook miRNAs that contribute to oncogenesis. Our method applied to a model of prostate cancer progression was able to identify miRNAs with roles in prostate cancer development.
Highlights
Despite the lack of agreement on their exact roles, it is known that miRNAs contribute to cancer progression
Results and discussion miRNAs regulate highly connected protein nodes and target pathways involved in cancer A protein-protein interaction network (PPI) was built from proven targets of known dysregulated miRNAs involved in carcinogenesis of the prostate
Comparing the average node of proteins within a PPI network built from proteins chosen at random to a network of proteins regulated by miRNAs reveals significant differences in the average node degree, closeness centrality and network stress (p-value
Summary
Despite the lack of agreement on their exact roles, it is known that miRNAs contribute to cancer progression. Many studies utilize methods to detect differential regulation of miRNA expression. This work uses a networks based approach to determine the sum node degree for all experimentally verified miRNA targets to identify potential regulators of prostate cancer initiation, progression and metastasis. Prostate cancer is a major medical problem for men around the world. 250,000 men will be diagnosed with prostate cancer this year and it is estimated that 35,000 will succumb to the disease. The most significant event during prostate cancer progression is metastatic dissemination [3]. Despite this significance, molecular events surrounding tumor progression and metastasis are poorly understood
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