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Targeting NF-?B in infantile hemangioma-derived stem cells reduces VEGF-A expression.

ABSTRACT: infantile hemangioma (IH) is a most common tumor of infancy. Using infantile hemangioma-derived stem cells (HemSCs), we recently demonstrated that corticosteroids suppress the expression of VEGF-A, monocyte chemoattractant protein-1 (MCP-1), urokinase plasminogen activator receptor (uPAR), and interleukin-6 (IL-6); each of these are known targets of the transcription factor nuclear factor ?-light-chain-enhancer of activated B cells (NF-?B). In the present study, we examined the expression of these NF-?B target genes in IH tissue specimens and the effect of NF-?B regulation on the expression of pro-angiogenic cytokines, and in particular VEGF-A, in HemSCs.RNA extracted from IH tissue and hemangioma-derived stem cells (HemSCs) was used to analyze NF-?B target gene expression by reverse transcription-quantitative PCR (RT-qPCR). The effects of NF-?B blockade were examined in HemSCs. Immunostaining, immunoblotting and ELISA were used to assess protein expression.MCP-1, uPAR, and IL-6 were found to be differentially expressed in proliferating versus involuting IH. Corticosteroids suppressed NF-?B activity of HemSCs. Velcade (Bortezomib), a proteosome inhibitor that can indirectly inhibit NF-?B, impaired HemSCs viability and expression of pro-angiogenic factors. Furthermore, specific inhibition of NF-?B resulted in suppression of VEGF-A.we demonstrate expression of NF-?B target genes in proliferating IH. In addition, we show that the expression of several pro-angiogenic factors in HemSCs, and in particular VEGF-A, is regulated by NF-B activity.

SUBMITTER: Greenberger S

PROVIDER: S-EPMC3034388 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Targeting NF-κB in infantile hemangioma-derived stem cells reduces VEGF-A expression.

Greenberger Shoshana S Adini Irit I Boscolo Elisa E Mulliken John B JB Bischoff Joyce J

Angiogenesis 20100925 4

<h4>Background</h4>infantile hemangioma (IH) is a most common tumor of infancy. Using infantile hemangioma-derived stem cells (HemSCs), we recently demonstrated that corticosteroids suppress the expression of VEGF-A, monocyte chemoattractant protein-1 (MCP-1), urokinase plasminogen activator receptor (uPAR), and interleukin-6 (IL-6); each of these are known targets of the transcription factor nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB). In the present study, we examined th ...[more]

PMID: 20872175

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Project description:Background Propranolol is a first-line clinical drug for infantile haemangiomas (IH) therapy. Nevertheless, resistance to propranolol is observed in some patients with IH. Circular RNAs (circRNAs) has been increasingly reported to act as a pivotal regulator in tumor progression. However, the underlying mechanism of circRNAs in IH remains unclear. Methods Quantitative real-time polymerase chain reaction was performed to detect Circ_0000915, miR-890 and RNF187 expression. Protein levels were determined using western blot. CCK-8 assay was used to measure cell proliferation. Caspase-3 activity assay and flow cytometry were conducted to determine cell apoptosis. Luciferase reporter assay was carried out to assess the interaction between miR-890 and Circ_0000915 or RNF187. Chromatin immunoprecipitation assay was performed to detect the interaction between STAT3 and Circ_0000915 promoter. Biotin pull-down assay was used to detect the direct interaction between miR-890 and Circ_0000915. In vivo experiments were performed to measure tumor formation. Results Here, we discovered depletion of Circ_0000915 increased propranolol sensitivity of haemangioma derived stem cells (HemSCs) both in vitro and in vivo, whereas forced expression of Circ_0000915 exhibited opposite effects. Mechanistically, Circ_0000915, transcriptionally induced by IL-6/STAT3 pathway, competed with RNF187 for the biding site in miR-890, led to upregulation of RNF187 by acting as a miR-890 “sponge”. Furthermore, silence of miR-890 reversed increased propranolol sensitivity of HemSCs due to Circ_0000915 ablation. Moreover, increased Circ_0000915 and RNF187 levels were observed in IH tissues and positively associated with propranolol resistance, miR-890 exhibited an inverse expression pattern. Conclusion We thereby uncover the activation of IL-6/STAT3/Circ_0000915/miR-890/RNF187 axis in propranolol resistance of IH, and provide therapeutic implications for patients of IH with propranolol resistance. Supplementary Information The online version contains supplementary material available at 10.1186/s40246-022-00416-w.

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Targeting NF-?B in infantile hemangioma-derived stem cells reduces VEGF-A expression.

Publications

Targeting NF-κB in infantile hemangioma-derived stem cells reduces VEGF-A expression.

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