Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Identification of cell signaling pathway associated miRNAs in cancer cells using a systems biological approach: potent RNAi response in cancer using novel 2â-OMe-phosphorodithioated modified siRNAs

ABSTRACT: MicroRNAs (miRNAs) are single-stranded, non-coding RNA molecules and on average only 22 nucleotides long that regulate gene expression at the post-transcriptional level. Target predictions of miRNA based on sequence are limited due to too many candidates resulting in high false positives. We generated the Association score matrix and miRNA-pathway association map. To validate our approach, we used miR-500 as an example to investigate the hypothetical target regulation mechanisms. We confirmed in-vitro that mir-500 highly is associated with ERK signaling pathway in breast cancer cells. Furthermore, we found PPFIA1 might be one of direct targets of miR-500 to regulate activating the ERK pathway. In conclusion, we developed a model system to systematically predict potential miRNA functional targets which play critical roles in cell signaling pathways from the NCI-60 genomic and proteomic data at whole genomic scale. Two groups of samples are included: 1. siControl treated control-miRNA and 2. mimic miR-500 treated two cells: MCF7 and MDA-MB-231. Gene expression profiles of mimic miR-500 treated cells were compared to that of control treated cells.

ORGANISM(S): Homo sapiens

SUBMITTER: Sangbae Kim

PROVIDER: E-GEOD-61752 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disorder, characterized by cardiomyocyte hypertrophy, cardiomyocyte disarray and fibrosis, which has a prevalence of ~1:200-500 and predisposes individuals to sudden death and heart failure. The mechanisms through which diverse HCM-causing mutations cause cardiac dysfunction remain mostly unknown and their identification may reveal new therapeutic avenues. MicroRNAs have emerged as critical regulators of gene expression and disease phenotype in various pathologies. We explored whether miRNAs could play a role in HCM pathogenesis and offer potential therapeutic targets. Methods and Results: Using high-throughput miRNA expression profiling and qPCR analysis in two distinct mouse models of HCM, we found that miR-199a-3p expression levels are upregulated in mutant mice compared to age- and treatment-matched wild-type mice. We also found that miR-199a-3p expression is enriched in cardiac non-myocytes compared to cardiomyocytes. When we expressed miR-199a-3p mimic in cultured primary cardiac non-myocytes and analyzed the conditioned media by proteomics, we found that several ECM proteins (e.g., TSP2, FBLN3, COL11A1, LYOX) were differentially expressed. We confirmed our proteomics findings by qPCR analysis of selected mRNAs and demonstrated that miR-199a-3p mimic expression in cardiac non-myocytes drives upregulation of ECM genes including Tsp2, Fbln3, Pcoc1, Col1a1 and Col3a1. To examine the role of miR-199a-3p in vivo, we inhibited its function using lock-nucleic acid (LNA)-based inhibitors (antimiR-199a-3p) in an HCM mouse model. Our results revealed that progression of cardiac fibrosis is attenuated when miR-199a-3p function is inhibited in mild-to-moderate HCM. Finally, guided by computational target prediction algorithms, we identified mRNAs Cd151 and Itga3 as direct targets of miR-199a-3p and have shown that miR-199a-3p mimic expression negatively regulates AKT activation in cardiac non-myocytes. Conclusions: Altogether, our results suggest that miR-199a-3p may contribute to cardiac fibrosis in HCM through its actions in cardiac non-myocytes. Thus, inhibition of miR-199a-3p in mild-to-moderate HCM may offer therapeutic benefit in combination with complementary approaches that target the primary defect in cardiac myocytes.

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Identification of cell signaling pathway associated miRNAs in cancer cells using a systems biological approach: potent RNAi response in cancer using novel 2â-OMe-phosphorodithioated modified siRNAs

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Identification of cell signaling pathway associated miRNAs in cancer cells using a systems biological approach: potent RNAi response in cancer using novel 2â-OMe-phosphorodithioated modified siRNAs