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Abstract Title:

1,25-Dihydroxy vitamin D prevents tumorigenesis by inhibiting oxidative stress and inducing tumor cellular senescence in mice.

Abstract Source:

Int J Cancer. 2018 Feb 14. Epub 2018 Feb 14. PMID: 29441580

Abstract Author(s):

Lulu Chen, Renlei Yang, Wanxin Qiao, Xiaoqin Yuan, Shui Wang, David Goltzman, Dengshun Miao

Article Affiliation:

Lulu Chen

Abstract:

Human epidemiological studies suggest that 1,25(OH)Ddeficiency might increase cancer incidence, but no spontaneous tumors have been reported in mice lacking 1,25(OH)Dor deficient in its receptor. In this study, we detected, for the first time, diverse types of spontaneous tumors in l,25(OH)Ddeficient 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)Dprevented spontaneous tumor development. We also demonstrated that l,25(OH)Ddeficiency 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)Dor 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)Ddeficiency 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)Dprevented spontaneous tumor development, suggesting that this inhibitory effect prevents the initiation and progression of tumorigenesis, thus provides a mechanistic basis for 1,25(OH)Dto prevent tumorigenesis in an aging organism. This article is protected by copyright. All rights reserved.

Study Type : Animal Study

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