The candidate oncogene CYP24A1: A potential biomarker for colorectal tumorigenesis

Abstract

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.

Figure 1

Immunhistochemical staining of CYP24A1 (A,C,E) and Ki-67 (B,D) in a colon adenoma (A,B), an adenocarcinoma (C,D), and a carcinoma with adjacent apparently normal colon mucosa (E). CYP24A1 positive (F) and negative control (G) in normal kidney. Double staining for CYP24A1 (brown) and vitamin D receptor (red) (H,I). Nuclei are counterstained with hematoxylin (blue). Insets in A,C,H, magnification of boxed areas in those panels. Bars: A–D,F,G = 20 μm; E =100 μm; H,I =10 μm.