Increased Expression of 25-Hydroxyvitamin D-1α-Hydroxylase in Dysgerminomas

Evans, Katie N.; Taylor, Harris C.; Zehnder, Daniel; Kilby, Mark; Bulmer, Judith N.; Shah, Farah; Adams, John S.; Hewison, Martin

doi:10.1016/s0002-9440(10)63343-3

Cited by 76 publications

(60 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This study thus provided a clear demonstration of the dependence of immune responses on circulating 25D levels. Similarly, stimulation of the TLR4/ CD14 receptor complexes by lipopolysaccharide induces CYP27B1 expression (84; unpublished results), consistent with correlations that other workers have found between TLR4 and CYP27B1 expression (27,28).…”

Section: Vitamin D Signaling and Metabolism In The Immune Systemsupporting

confidence: 87%

Vitamin D Signaling, Infectious Diseases, and Regulation of Innate Immunity

2008

View full text Add to dashboard Cite

Vitamin D was first identified as a cure for nutritional rickets, a disease of bone growth caused by an inadequate uptake of dietary calcium. It is now known that vitamin D can be obtained through two independent pathways: limited dietary sources and the photochemical action of solar UV light in the skin. Cod liver oil was discovered to be an excellent source of antirachitic activity in 1827, although it was not until several decades later that the active ingredient was identified as vitamin D 3 . Even earlier, in 1822, a Polish physician studying children reached the remarkable conclusion that sunlight cured rickets after noting that rickets was relatively rare in the clearer air of rural areas. Almost 100 years later, in 1919, it was shown that artificial UV light cured rickets (49; www .beyonddiscovery.org/Includes/DBLink.asp?IDϭ1176). Indeed, secosteroidal vitamin D 3 is produced in the skin via photochemical and thermal conversion of 7-dehydrocholesterol in the presence of UVB light (ϳ295 to 320 nm). While it seems that vitamin D is readily accessible via dietary or solar routes, vitamin D insufficiency or deficiency is, in fact, quite widespread. Solar UVB irradiation is absorbed by atmospheric ozone; consequently, the surface intensity of UVB varies markedly with latitude and time of year. Moreover, as vitamin D intake is generally inadequate in most diets (38-40), the rate of vitamin D insufficiency or deficiency increases with increasing latitude.The term vitamin D refers collectively to vitamin D 3 and vitamin D 2 , which is derived from irradiation of the steroid ergosterol in yeast. Biologically active vitamin D is generated via largely hepatic 25-hydroxylation catalyzed by CYP2R1, CYP27A1, and possibly other enzymes to produce 25-hydroxvitamin D (25D) (21,40,43,67,81), which has a long half-life and is the major circulating vitamin D metabolite. 25D is modified by 1␣-hydroxylation catalyzed by CYP27B1, which produces hormonal 1,25-dihydroxyvitamin D (1,25D) (40,43,67). Vitamin D compounds are catabolized via 24-hydroxylation by CYP24, whose expression is strongly inducible by 1,25D, which constitutes a negative feedback loop (40,43,67).While the kidneys are a major site of 1␣-hydroxylation of 25D, it has recently become clear that generation of hormonal 1,25D in peripheral tissues is critical to the full scope of the physiological actions of this compound. Renal 1␣-hydroxylation is tightly controlled by calcium homeostatic signals, particularly circulating parathyroid hormone (PTH). Although initially characterized as a calcium homeostatic agent, vitamin D is now known to have pleiotropic actions, including a key role in immune system regulation (49). Importantly in this regard, recent research detailed here has uncovered critical, cell-specific differences in both the regulation of 1␣-hydroxylation of 25D and 24-hydroxylation that are relevant to the role of 1,25D as an immune system regulator. VITAMIN D INSUFFICIENCY/DEFICIENCY AND DISEASEWhile there is no strict definition, vitamin D deficiency i...

show abstract

Section: Vitamin D Signaling and Metabolism In The Immune Systemsupporting

confidence: 87%

Vitamin D Signaling, Infectious Diseases, and Regulation of Innate Immunity

2008

View full text Add to dashboard Cite

show abstract

“…3D) data may reflect inherent differences in 1a-hydroxylase transactivation: recent studies have characterized polymorphisms within the gene for 1a-hydroxylase (CYP27B1), which may confer variability in the regulation of 1a-hydroxylase expression (47). The underlying basis for up-regulation of 1a-hydroxylase in breast tumors is also clear, but we have observed a similar induction of 1a-hydroxylase in lymphomas (37) and dysgerminomas (48). In these cases, synthesis of 1,25(OH) 2 D 3 was mediated via expression of 1a-hydroxylase in tumor-associated macrophages, and a similar pattern of increased expression of 1a-hydroxylase has also been reported in alveolar macrophages associated with lung cancer (49).…”

Section: Vitamin D Metabolism In Breast Cancermentioning

confidence: 55%

Autocrine Metabolism of Vitamin D in Normal and Malignant Breast Tissue

Townsend

Banwell

Guy

et al. 2005

Clinical Cancer Research

Self Cite

165

138

View full text Add to dashboard Cite

Purpose: Vitamin D seems to exert a protective effect against common cancers, although this does not correlate with circulating levels of active 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], indicating a more localized activation of vitamin D. The aim of this study was to investigate the significance of this in breast cancer. Experimental Design: Quantitative reverse transcription-PCR analysis of mRNA expression was carried out for the vitamin D^activating enzyme 1a-hydroxylase, the catabolic enzyme 24-hydroxylase, and the vitamin D receptor in 41tumors and paired nonneoplastic tissue as well as breast cancer cell lines. Immunohistochemistry was used to assess 1a-hydroxylase protein expression, and enzyme assays were used to quantify vitamin D metabolism.Results: Expression of mRNA for 1a-hydroxylase (27-fold; P < 5 Â 10 À11), vitamin D receptor (7-fold; P < 1.5 Â 10 À8 ), and 24-hydroxylase (4-fold; P < 0.02) was higher in breast tumors. 1a-Hydroxylase enzyme activity was also higher in tumors (44.3 F 11.4 versus12.4 F 4.8 fmol/h/mg protein in nonneoplastic tissue; P < 0.05). However, production of inactive 1,24,25-trihydroxyvitamin D 3 was also significantly higher in tumors (84.8 F 11.7 versus 33.6 F 8.5fmol/h/mg protein; P < 0.01). Antisense inhibition of 24-hydroxylase in vitro increased antiproliferative responses to 1,25(OH) 2 D 3 . Conclusion: These data indicate that the vitamin D^activating enzyme 1a-hydroxylase is upregulated in breast tumors. However, dysregulated expression of 24-hydroxylase seems to abrogate the effects of local 1,25(OH) 2 D 3 production in tumors by catalyzing catabolism to less active vitamin D metabolites.The enzymes involved in autocrine metabolism of vitamin D in breast tissue may therefore provide important targets for both the prevention and treatment of breast cancer.

show abstract

“…Since the patient described here was pregnant and had no phenotypical signs that would suggest relevant syndromic data, she was not asked about, or assessed for, this possibility. An association between dysgerminoma and malignant hypercalcemia 10,18,19 has been described by some authors, but in this case tests showed that the patient was within normal limits. Another peculiarity that attracts attention is the association with dysgerminoma described in some varieties of animals 20,21 .…”

Section: Imaging In Medicine Introductionmentioning

confidence: 57%