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Integrative network-based analysis of mRNA and microRNA expression in 1,25-dihydroxyvitamin D3-treated cancer cells.

Kutmon M, Coort SL, de Nooijer K, Lemmens C, Evelo CT - Genes Nutr (2015)

Bottom Line: Pathway analysis revealed 15 significantly altered pathways: eight more general mostly cell cycle-related pathways and seven cancer-specific pathways.Adding microRNA regulation to the network enabled the identification of gene targets of significantly expressed microRNAs after 1,25(OH)2D3 treatment.Six of the nine differentially expressed microRNAs target genes in the extended network, including CLSPN, an important checkpoint regulator in the cell cycle that was down-regulated, and FZD5, a receptor for Wnt proteins that was up-regulated.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioinformatics - BiGCaT, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht, The Netherlands, martina.kutmon@maastrichtuniversity.nl.

ABSTRACT
Nutritional systems biology is an evolving research field aimed at understanding nutritional processes at a systems level. It is known that the development of cancer can be influenced by the nutritional status, and the link between vitamin D status and different cancer types is widely investigated. In this study, we performed an integrative network-based analysis using a publicly available data set studying the role of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in prostate cancer cells on mRNA and microRNA level. Pathway analysis revealed 15 significantly altered pathways: eight more general mostly cell cycle-related pathways and seven cancer-specific pathways. The changes in the G1-to-S cell cycle pathway showed that 1,25(OH)2D3 down-regulates the genes influencing the G1-to-S phase transition. Moreover, after 1,25(OH)2D3 treatment the gene expression in several cancer-related processes was down-regulated. The more general pathways were merged into one network and then extended with known protein-protein and transcription factor-gene interactions. Network algorithms were used to (1) identify active network modules and (2) integrate microRNA regulation in the network. Adding microRNA regulation to the network enabled the identification of gene targets of significantly expressed microRNAs after 1,25(OH)2D3 treatment. Six of the nine differentially expressed microRNAs target genes in the extended network, including CLSPN, an important checkpoint regulator in the cell cycle that was down-regulated, and FZD5, a receptor for Wnt proteins that was up-regulated. The extendable network-based tools PathVisio and Cytoscape enable straightforward, in-depth and integrative analysis of mRNA and microRNA expression data in 1,25(OH)2D3-treated cancer cells.

No MeSH data available.


Related in: MedlinePlus

Vitamin D-microRNA network. MicroRNA–target interactions from TargetScan and miRTarBase were added to the vitamin D-extended network. Six out of nine differentially expressed microRNAs in 1,25(OH)2D3-treated cancer cells were present in the vitamin D-microRNA network. Those six up-regulated microRNAs are highlighted as green rounded rectangles. Together they target 96 gene products present in pathways (diamonds) and added with protein–protein and transcription factor–gene interactions (ellipses). Up-regulated genes are coloured in red, and down-regulated genes are coloured in blue. The edge colour indicates the source, either TargetScan (blue) or miRTarBase (red). Seven target interactions are present in both databases
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Fig4: Vitamin D-microRNA network. MicroRNA–target interactions from TargetScan and miRTarBase were added to the vitamin D-extended network. Six out of nine differentially expressed microRNAs in 1,25(OH)2D3-treated cancer cells were present in the vitamin D-microRNA network. Those six up-regulated microRNAs are highlighted as green rounded rectangles. Together they target 96 gene products present in pathways (diamonds) and added with protein–protein and transcription factor–gene interactions (ellipses). Up-regulated genes are coloured in red, and down-regulated genes are coloured in blue. The edge colour indicates the source, either TargetScan (blue) or miRTarBase (red). Seven target interactions are present in both databases

Mentions: Using the CyTargetLinker app in Cytoscape, a regulatory layer of microRNAs was added to the network. One thousand four hundred and thirty-nine microRNA nodes and 25,886 microRNA–target interactions were found when combining the information from the prediction database TargetScan (version 6.2—23,091 interaction) and the validated database miRTarBase (version 4.5—2795 interactions). Six of the nine differentially expressed microRNAs in the data set were found in this new vitamin D-microRNA network, hsa-miR-29a, hsa-miR-371-5p, hsa-miR-1915, hsa-miR-663, hsa-miR-134 and hsa-miR-542-5p. All six are up-regulated in 1,25(OH)2D3-treated cancer cells. Consequently, we selected the six up-regulated microRNAs in the network and created a subnetwork with all their targets in the network (see Fig. 4). All microRNAs target genes in the pathways (diamonds) and extended first neighbours (ellipses).Fig. 4


Integrative network-based analysis of mRNA and microRNA expression in 1,25-dihydroxyvitamin D3-treated cancer cells.

Kutmon M, Coort SL, de Nooijer K, Lemmens C, Evelo CT - Genes Nutr (2015)

Vitamin D-microRNA network. MicroRNA–target interactions from TargetScan and miRTarBase were added to the vitamin D-extended network. Six out of nine differentially expressed microRNAs in 1,25(OH)2D3-treated cancer cells were present in the vitamin D-microRNA network. Those six up-regulated microRNAs are highlighted as green rounded rectangles. Together they target 96 gene products present in pathways (diamonds) and added with protein–protein and transcription factor–gene interactions (ellipses). Up-regulated genes are coloured in red, and down-regulated genes are coloured in blue. The edge colour indicates the source, either TargetScan (blue) or miRTarBase (red). Seven target interactions are present in both databases
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4537452&req=5

Fig4: Vitamin D-microRNA network. MicroRNA–target interactions from TargetScan and miRTarBase were added to the vitamin D-extended network. Six out of nine differentially expressed microRNAs in 1,25(OH)2D3-treated cancer cells were present in the vitamin D-microRNA network. Those six up-regulated microRNAs are highlighted as green rounded rectangles. Together they target 96 gene products present in pathways (diamonds) and added with protein–protein and transcription factor–gene interactions (ellipses). Up-regulated genes are coloured in red, and down-regulated genes are coloured in blue. The edge colour indicates the source, either TargetScan (blue) or miRTarBase (red). Seven target interactions are present in both databases
Mentions: Using the CyTargetLinker app in Cytoscape, a regulatory layer of microRNAs was added to the network. One thousand four hundred and thirty-nine microRNA nodes and 25,886 microRNA–target interactions were found when combining the information from the prediction database TargetScan (version 6.2—23,091 interaction) and the validated database miRTarBase (version 4.5—2795 interactions). Six of the nine differentially expressed microRNAs in the data set were found in this new vitamin D-microRNA network, hsa-miR-29a, hsa-miR-371-5p, hsa-miR-1915, hsa-miR-663, hsa-miR-134 and hsa-miR-542-5p. All six are up-regulated in 1,25(OH)2D3-treated cancer cells. Consequently, we selected the six up-regulated microRNAs in the network and created a subnetwork with all their targets in the network (see Fig. 4). All microRNAs target genes in the pathways (diamonds) and extended first neighbours (ellipses).Fig. 4

Bottom Line: Pathway analysis revealed 15 significantly altered pathways: eight more general mostly cell cycle-related pathways and seven cancer-specific pathways.Adding microRNA regulation to the network enabled the identification of gene targets of significantly expressed microRNAs after 1,25(OH)2D3 treatment.Six of the nine differentially expressed microRNAs target genes in the extended network, including CLSPN, an important checkpoint regulator in the cell cycle that was down-regulated, and FZD5, a receptor for Wnt proteins that was up-regulated.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioinformatics - BiGCaT, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht, The Netherlands, martina.kutmon@maastrichtuniversity.nl.

ABSTRACT
Nutritional systems biology is an evolving research field aimed at understanding nutritional processes at a systems level. It is known that the development of cancer can be influenced by the nutritional status, and the link between vitamin D status and different cancer types is widely investigated. In this study, we performed an integrative network-based analysis using a publicly available data set studying the role of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in prostate cancer cells on mRNA and microRNA level. Pathway analysis revealed 15 significantly altered pathways: eight more general mostly cell cycle-related pathways and seven cancer-specific pathways. The changes in the G1-to-S cell cycle pathway showed that 1,25(OH)2D3 down-regulates the genes influencing the G1-to-S phase transition. Moreover, after 1,25(OH)2D3 treatment the gene expression in several cancer-related processes was down-regulated. The more general pathways were merged into one network and then extended with known protein-protein and transcription factor-gene interactions. Network algorithms were used to (1) identify active network modules and (2) integrate microRNA regulation in the network. Adding microRNA regulation to the network enabled the identification of gene targets of significantly expressed microRNAs after 1,25(OH)2D3 treatment. Six of the nine differentially expressed microRNAs target genes in the extended network, including CLSPN, an important checkpoint regulator in the cell cycle that was down-regulated, and FZD5, a receptor for Wnt proteins that was up-regulated. The extendable network-based tools PathVisio and Cytoscape enable straightforward, in-depth and integrative analysis of mRNA and microRNA expression data in 1,25(OH)2D3-treated cancer cells.

No MeSH data available.


Related in: MedlinePlus