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

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s12263-015-0484-0) contains supplementary material, which is available to authorized users.

Vitamin D limits inflammation-linked microRNA expression in adipocytes in vitro and in vivo: A new mechanism for the regulation of inflammation by vitamin D

“…The modulation of miRs by VD is reported here for the first time in the context of obesity-associated comorbidities; similar ability has been widely described in cancer context. Indeed, differential regulation of miR expression profiles by 1,25(OH) 2 D has been demonstrated in prostate cancer cells [40], bladder cancer cells [41], and in lung cancer [42].…”

Immunometabolic effects of vitamin D unravelled by an integrative systems biology analysis

“…In THP-1 cells only, 1,25(OH) 2 D3 potently regulated genes involved in progression of cell cycle and DNA replication, consistent with the neoplastic origin of these cells. The pathways with high Z-score include retinoblastoma in cancer, G1 to S cell cycle control, DNA replication and cell cycle, are similar to those reported previously for prostate cancer cells treated with 1,25(OH) 2 D3[132]. This suggests that, in addition to its common metabolic innate immune targets, 1,25(OH) 2 D3 also has common antiproliferative targets in neoplastic cell types, including suppression of key proteins that participate in progression of the cell cycle and regulation of DNA replication[129].…”

“…Furthermore, studies in the last two decades have explored the anti-proliferative properties of vitamin D in malignant neoplastic cells [54] [130]. Notably, two studies (one of them discussed in Chapter 4) carried out a similar pathway analysis that described in this thesis and showed that 1,25(OH) 2 D3 represses gene expression of cell cycle components in prostate and myeloid cancer cell lines [132] [81]. Finally, throughout this thesis we will explain in more detail the role of vitamin D in the immune system, showing that its different immunomodulatory roles, depending on immune cell type, have the potential to generate a specific immune response.…”

“…This suggests that, in addition to its common metabolic innate immune targets, 1,25(OH) 2 D3 also has common antiproliferative targets in neoplastic cell types, including suppression of key proteins that participate in progression of the cell cycle and regulation of DNA replication[129]. Interestingly, pathway analysis of 1,25(OH) 2 D3 in prostate cancer cells[132] did not reveal any significant regulation of the metabolic pathways as identified for monocytes and DCs in the current study. Thus, in the same way that suppression of cell cycle/DNA replication genes appears to be a cancer cell-specific effect of 1,25(OH) 2 D3, genes associated with oxidative phosphorylation and energy metabolism appear to be innate immune cell specific.…”

Human nutrition, environment, and health

“…Kutmon et al uses a publicly available data set of changes in transcript and microRNA abundances in prostate cancer cells treated with 1,25-dihydroxyvitamin D3 (Kutmon et al 2015). PathVisio and Cytoscape network tools identified cell cycle and cancer-specific pathways altered by this vitamin.…”