Abstract
Human epidemiological studies suggest that 1,25(OH)2D3 deficiency might increase cancer incidence, but no spontaneous tumors have been reported in mice lacking 1,25(OH)2D3 or deficient in its receptor. In this study, we detected, for the first time, diverse types of spontaneous tumors in l,25(OH)2D3 deficient mice more than 1-year of age. This was associated with increased oxidative stress, cellular senescence and senescence-associated secretory phenotype molecules, such as hepatocyte growth factor, mediated via its receptor c-Met. Furthermore, 1,25(OH)2D3 prevented spontaneous tumor development. We also demonstrated that l,25(OH)2D3 deficiency accelerates allograft tumor initiation and growth by increasing oxidative stress and DNA damage, activating oncogenes, inactivating tumor suppressor genes, stimulating malignant cell proliferation and inhibiting their senescence; in contrast, supplementation with exogenous l,25(OH)2D3 or antioxidant, or knock-down of the Bmi1 or c-Met oncogene, largely rescued the phenotypes of allograft tumors. Results from this study suggest that 1,25(OH)2D3 deficiency enhances tumorigenesis by increasing malignant cell oxidative stress and DNA damage, stimulating microenvironmental cell senescence and a senescence-associated secretory phenotype, and activating oncogenes and inactivating tumor suppressor genes, thus increasing malignant cell proliferation. This study provides direct evidence supporting the role of vitamin D deficiency in increasing cancer incidence. Conversely, 1,25(OH)2D3 prevented spontaneous tumor development, suggesting that this inhibitory effect prevents the initiation and progression of tumorigenesis, thus provides a mechanistic basis for 1,25(OH)2D3 to prevent tumorigenesis in an aging organism. This article is protected by copyright. All rights reserved.
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