Expression of vitamin D receptor and 25-hydroxyvitamin D3-1 alpha-hydroxylase in normal and malignant human colon
ABSTRACT Considerable evidence exists to support the use of vitamin D to prevent and/or treat colorectal cancer. However, the routine use of bioactive vitamin D, 1,25-dihydroxyvitamin D3, is limited by the side effect of toxic hypercalcemia. Recent studies, however, suggest that colonic epithelial cells express 25-hydroxyvitamin D3-1alpha-hydroxylase, an enzyme that converts nontoxic pro-vitamin D, 25-hydroxycholecalciferol [25(OH)D3], to its bioactive form. Yet, nothing is known as to the cellular expression of 1alpha-hydroxylase and the vitamin D receptor (VDR) in the earliest histopathologic structures associated with malignant transformation such as aberrant crypt foci (ACF) and polyps [addressing the possibility of using nontoxic 25(OH)D3 for chemoprevention], nor is anything known as to the expression of these proteins in colorectal cancer as a function of tumor cell differentiation or metastasis [relevant to using 25(OH)D3 for chemotherapy]. In this study, we show that 1alpha-hydroxylase is present at equal high levels in normal colonic epithelium as in ACFs, polyps, and colorectal cancer irrespective of tumor cell differentiation. In contrast, VDR levels were low in normal colonic epithelial cells; were increased in ACFs, polyps, and well-differentiated tumor cells; and then declined as a function of tumor cell de-differentiation. Both 1alpha-hydroxylase and VDR levels were negligible in tumor cells metastasizing to regional lymph nodes. Overall, these data support using 25(OH)D3 for colorectal cancer chemoprevention but suggest that pro-vitamin D is less likely to be useful for colorectal cancer chemotherapy.
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ABSTRACT: Traditionally the main recognized function of vitamin D has been calcium and phosphate homeostasis. Nevertheless, recent evidences have highlighted the importance of vitamin D3 as a protective agent against various cancers. The association between CRC and vitamin D3 was first suggested in ecologic studies, but further was confirmed by observational studies in humans and experimental studies in both animal models and cellular lines. The protective role of vitamin D3 against cancer has been attributed to its influence of on cell proliferation, differentiation, apoptosis, DNA repair mechanisms, inflammation and immune function. In its active (calcitriol) form (1,25-dihydroxyvitamin D3[1α,25-(OH)2D3]) vitamin D3 and the nuclear vitamin D receptor (VDR) regulate hundreds of genes including those coding for proteins involved in cell differentiation and cell proliferation. The current review addresses some of the key mechanisms that influence the biological actions of vitamin D and its metabolites. The insights derived from these mechanisms may aid in designing new uses for this hormone and its non-hypercalcemic derivatives in the treatment and/or prevention of CRC.Critical reviews in oncology/hematology 08/2013; DOI:10.1016/j.critrevonc.2013.07.016 · 4.05 Impact Factor
Article: Vitamin D and Cancer[Show abstract] [Hide abstract]
ABSTRACT: Vitamin D system is a complex pathway that includes precursors, active metabolites, enzymes, and receptors. This complex system actives several molecular pathways and mediates a multitude of functions. In addition to the classical role in calcium and bone homeostasis, vitamin D plays "non-calcemic" effects in host defense, inflammation, immunity, and cancer processes as recognized in vitro and in vivo studies. The aim of this review is to highlight the relationship between vitamin D and cancer, summarizing several mechanisms proposed to explain the potential protective effect of vitamin D against the development and progression of cancer. Vitamin D acts like a transcription factor that influences central mechanisms of tumorigenesis: growth, cell differentiation, and apoptosis. In addition to cellular and molecular studies, epidemiological surveys have shown that sunlight exposure and consequent increased circulating levels of vitamin D are associated with reduced reduced occurrence and a reduced mortality in different histological types of cancer. Another recent field of interest concerns polymorphisms of vitamin D receptor (VDR); in this context, preliminary data suggest that VDR polymorphisms more frequently associated with tumorigenesis are Fok1, Bsm1, Taq1, Apa1, EcoRV, Cdx2; although further studies are needed to clarify their role in the cancer. In this review, the relationship between vitamin D and cancer is discussed.Frontiers in Endocrinology 04/2012; 3:58. DOI:10.3389/fendo.2012.00058
Article: Vitamin D and colon cancer[Show abstract] [Hide abstract]
ABSTRACT: The most active vitamin D metabolite, 1α,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), is a pleiotropic hormone with wide regulatory actions. Classically, vitamin D deficiency was known to alter calcium and phosphate metabolism and bone biology. In addition, recent epidemiological and experimental studies support the association of vitamin D deficiency with a large variety of human diseases, and particularly with the high risk of colorectal cancer. By regulating the expression of many genes via several mechanisms, 1,25(OH)(2)D(3) induces differentiation, controls the detoxification metabolism and cell phenotype, sensitises cells to apoptosis and inhibits the proliferation of cultured human colon carcinoma cells. Consistently, 1,25(OH)(2)D(3) and several of its analogues decrease intestinal tumourigenesis in animal models. Molecular, genetic and clinical data in humans are scarce but they suggest that vitamin D is protective against colon cancer. Clearly, the available evidence warrants new, well-designed, large-scale trials to clarify the role of vitamin D in the prevention and/or therapy of this important neoplasia.Endocrine Related Cancer 03/2012; 19(3):R51-71. DOI:10.1530/ERC-11-0388 · 4.91 Impact Factor