The Candidate Oncogene CYP24A1: A Potential Biomarker for Colorectal Tumorigenesis

Department of Medicine, Semmelweis University, Budapest, Hungary.
Journal of Histochemistry and Cytochemistry (Impact Factor: 1.96). 11/2009; 58(3):277-85. DOI: 10.1369/jhc.2009.954339
Source: PubMed


The main autocrine/paracrine role of the active metabolite of vitamin D(3), 1alpha,25-dihydroxyvitamin D(3) (1,25-D(3)), is inhibition of cell growth and induction of cell differentiation and/or apoptosis. Synthesis and degradation of the secosteroid occurs not only in the kidney but also in normal tissue or malignant extrarenal tissues such as the colon. Because 25-hydroxyvitamin D(3) 24-hydroxylase (CYP24A1) is considered to be the main enzyme determining the biological half-life of 1,25-D(3), we have examined expression of the CYP24A1 mRNA (by real-time RT-PCR) and protein (by immunohistochemistry) in normal human colon mucosa, colorectal adenomas, and adenocarcinomas in 111 patients. Although 76% of the normal and benign colonic tissue was either completely devoid of or expressed very low levels of CYP24A1, in the majority of the adenocarcinomas (69%), the enzyme was present at high concentrations. A parallel increased expression of the proliferation marker Ki-67 in the same samples suggests that overexpression of CYP24A1 reduced local 1,25-D(3) availability, decreasing its antiproliferative effect.

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    ABSTRACT: The vitamin D system is deregulated during development and progression of several cancer types. Data on the expression of the vitamin D system in the diseased pancreas are missing. The aim of this study was to investigate the expression of the vitamin D receptor (VDR), 1,25-dihydroxyvitamin D3 24-hydroxylase (CYP24A1), and the calcium-sensing receptor (CaSR), a vitamin D target gene, in the different regions of the pancreas in patients with chronic pancreatitis (n = 6) and pancreatic ductal adenocarcinomas (PDAC) (n = 17). We analyzed the expression of these genes at mRNA and protein level with quantitative real-time RT-PCR and immunostaining. mRNA expression of CYP24A1 and VDR was significantly increased in tumors compared with the adjacent non-tumorous tissue (p < 0.05), while CaSR mRNA expression decreased. Both the VDR and the CaSR protein were highly expressed in the endocrine compared with the exocrine pancreas. In CP the CYP24A1 expression was highest in the endocrine pancreas, while in PDACs in the transformed ducts. In the PDAC patients CYP24A1 expression in the islets was significantly lower than in CP patients. Our data suggest that during ductal adenocarcinoma development the vitamin D system in the pancreas becomes deregulated on two levels: in the islets CYP24A1 expression decreases weakening the negative feedback regulation of the vitamin D-dependent insulin synthesis/secretion. In the transformed ducts CYP24A1 expression increases, impairing the antiproliferative effect of vitamin D in these cells.
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    • "Yet, cyp24a1 is not only associated with a poor response to vitamin D3-based therapeutics, it rather appears to be overexpressed in various tumor types [35]–[37]. Along these lines, Horvath et al. recently proposed cyp24a1 as a novel biomarker for colon tumorigenesis [38]. They found highest cyp24a1 mRNA expression in benign colorectal lesions compared to normal colonic tissue and adenocarcinomas, while cyp24a1 protein expression was highest in advanced adenocarcinomas as compared to early stages or normal tissue. "
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    • "Several studies have focused on the dynamics of VDR, CYP24A1, and CYP27B1 in different cancer tissues such as breast, prostate, colon, and ovary (Segersten et al. 2005; McCarthy et al. 2009; Horvath et al. 2010), demonstrating altered expression in benign or malignant tumors. The current knowledge on the presence of locally altered vitamin D metabolism in benign and malignant thyroid tissue is limited . "
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