ABSTRACT
Hemangioma (HA) is a type of benign tumor common in infancy. The main feature of HA is the abnormal proliferation of vascular endothelial cells. To date, the pathogenesis of HA remains unclear. Fully understanding the process of HA tumorigenesis is essential for developing novel treatment for HAs. Dysregulation of microRNAs (miRNAs/miR) has been reported to be involved in the development of various diseases, including HA. In the present study, the expression of miR424 decreased in HAderived endothelial cells (HemECs). To elucidate the role of miR424 in HAs development, the present study overexpressed or inhibited miR424 in HemECs, revealing that miR424 overexpression significantly inhibited HemEC growth and promoted apoptosis, while the downregulation of miR424 promoted cell growth and inhibited cell apoptosis. To elucidate the underlying mechanism, bioinformatic analyses were performed, the result of which demonstrated that the 3'untranslated region of vascular endothelial growth factor receptor 2 (VEGFR2) may be a target of miR424. The result of a dual luciferase reporter assay confirmed that the expression of VEGFR2 was inhibited by miR424. In addition, it was revealed that the hyperphosphorylation of protein kinase B (AKT) and extracellular signalregulated kinase (ERK) in HemECs, and the restoration of miR424 markedly inhibited the activation of AKT and ERK. In conclusion, these results indicated that miR424 may target VEGFR2 and inhibit HemECs growth, and that low expression of miR424 in HemECs may lead to an increase in cell growth and a decrease in cell apoptosis. Thus, it was proposed that miR424 may serve as a tumor suppressor in HemECs, and that VEGFR2 may be a potential tumor suppressive target in HemECs and for the treatment of HA.
Subject(s)
Endothelial Cells/metabolism , Endothelial Cells/pathology , Hemangioma/genetics , Hemangioma/pathology , MicroRNAs/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolism , Apoptosis/genetics , Base Sequence , Cell Proliferation/genetics , Down-Regulation/genetics , Gene Expression Regulation, Neoplastic , Humans , MAP Kinase Signaling System , MicroRNAs/genetics , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolismABSTRACT
Folic acid supplementation may meliorate cardiovascular disease risk by improving vascular endothelial structure and function. However, the underlying mechanisms are still lack of a global understanding. To be used, folic acid must be converted to 7,8-dihydrofolate by dihydrofolate reductase to generate one-carbon derivatives serving as important cellular cofactors in the synthesis of nucleotides and amino acids required for cell growth. Therefore, this study explored the effect of dihydrofolate reductase knockdown on endothelial EA.hy926 cell growth and the mechanism involved. We found that down-regulation of dihydrofolate reductase inhibited EA.hy926 cell proliferation, and induced G1 phase arrest. Meanwhile, the expression of regulators necessary for G1/S phase transition, such as cyclin-dependent kinases CDK2, CDK4 and CDK6, were remarkably down-regulated; by contrast, the cell cycle inhibitors p21(waf/cip1), p27(Kip1) and p53 were significantly up-regulated after dihydrofolate reductase knockdown. Furthermore, supplementation of 5-methyltetrahydrofolate to the dihydrofolate reductase knockdown cells could weaken the inhibitory effect of dihydrofolate reductase knockdown on cell proliferation, simultaneously, inducing the expression of p53 and p21(waf/cip1) falling back moderately. Our findings suggest that attenuating dihydrofolate reductase may cause imbalanced expression of cell cycle regulators, especially up-regulation of p53-p21(waf/cip1) pathway, leading to G1 cell cycle arrest, thereby inhibiting the growth of endothelial EA.hy926 cells.
ABSTRACT
Infantile haemangiomas (IH) are common benign vascular tumors of childhood. They are characterised by rapid growth during the first year of life and slow regression that is usually completed by 7-10 years of age. The underlying mechanism of action of IH is aberrant angiogenesis and vasculogenesis, and involves the mammalian target of rapamycin pathway and vascular endothelial growth factor pathway. IH become a challenge if they are part of a syndrome, are located in certain areas of the body, or if complications develop. The beta-adrenergic receptor blocker propranolol is a promising new candidate for first-line systemic therapy. This review focuses on the clinical characteristics, pathogenesis and management of IH.