Increased copy-number and not DNA hypomethylation causes overexpression of the candidate proto-oncogene CYP24A1 in colorectal cancer.
Increased copy-number and not DNA hypomethylation causes overexpression of the candidate proto-oncogene CYP24A1 in colorectal cancer.
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DOI：
10.1002/ijc.28143
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发表时间：
2013-09-15
影响因子：
6.4
通讯作者：
Kallay, Enikoe
中科院分区：
文献类型：
--
作者：
Hoebaus, Julia;Hummel, Doris M.;Thiem, Ursula;Fetahu, Irfete S.;Aggarwal, Abhishek;Muellauer, Leonhard;Heller, Gerwin;Egger, Gerda;Mesteri, Ildiko;Baumgartner-Parzer, Sabina;Kallay, Enikoe
在结直肠癌 (CRC) 中，维生素 D 分解代谢酶 1,25-二羟基维生素 D 24-羟化酶 (CYP24A1) 过度表达，对 1,25-二羟基维生素 D3 (1,25-D3) 的分解代谢具有潜在的显着积极影响。然而，人们对 CYP24A1 过度表达的潜在机制知之甚少。在本研究中，我们调查了可能的原因，包括 CYP24A1 启动子的低甲基化、CYP24A1 基因位点 (20q13.2) 的扩增以及 CYP24A1 特异性转录因子的表达改变。我们定量了 CYP24A1 基因拷贝数，对 CYP24A1 启动子进行亚硫酸氢盐测序以评估 DNA 甲基化，并测量 CYP24A1、25-羟基维生素 D 1α-羟化酶 (CYP27B1)、维生素 D 受体 (VDR) 和类视黄醇 X 受体 (RXR) 的 mRNA 表达。我们发现 127 个结直肠肿瘤中有 77 个 (60%) 显示 CYP24A1 基因拷贝数增加，并且超过 6 个 CYP24A1 拷贝与 CYP24A1 mRNA 表达呈正相关，表明存在因果关系。同一患者的肿瘤组织和邻近粘膜之间以及 mRNA 高表达或低表达的组织之间未发现 CYP24A1 启动子甲基化存在差异，因此排除了 DNA 低甲基化作为 CRC 中 CYP24A1 过表达的可能原因。此外，参与复制许可的几种因子的 mRNA 表达与 CYP24A1 mRNA 表达呈正相关，这提高了 CYP24A1 过表达可能通过抑制局部 1,25-D3 水平有利于肿瘤增殖增加的可能性。我们得出结论，高拷贝数增益是 CRC 中 CYP24A1 过度表达的关键决定因素。 CYP24A1 过表达的其他假定原因，包括启动子低甲基化和 VDR 和/或 RXR 表达增强，似乎并未涉及其中。什么是新的？最近，有人提出结直肠癌与循环维生素 D 水平降低之间的关联可能与肿瘤中维生素 D 分解代谢酶 CYP24A1 的过度表达有关。在寻找机制解释的过程中，CYP24A1 基因拷贝数的增加与该酶在 60% 的结直肠肿瘤中的过度表达有关，并且表达与增殖标志物密切相关。研究结果表明，CYP24A1 过度表达可能会消耗肿瘤骨化三醇（1,25-二羟基维生素 D3）水平，从而可能增加肿瘤的增殖潜力。
In colorectal cancer (CRC) the vitamin D catabolizing enzyme 1,25-dihydroxyvitamin D 24-hydroxylase (CYP24A1) is overexpressed with a potentially significant, positive impact on the catabolism of 1,25-dihydroxyvitamin D3 (1,25-D3). However, the underlying mechanism of CYP24A1 overexpression is poorly understood. In the present study, we investigated possible causes including hypomethylation of the CYP24A1 promoter, amplification of the CYP24A1 gene locus (20q13.2), and altered expression of CYP24A1-specific transcription factors. We quantified CYP24A1 gene copy-number, performed bisulfite sequencing of the CYP24A1 promoter to assess DNA methylation, and measured mRNA expression of CYP24A1, 25-hydroxyvitamin D 1α-hydroxylase (CYP27B1), vitamin D receptor (VDR) and retinoid X receptor (RXR). We found that 77 (60%) out of 127 colorectal tumors showed increased CYP24A1 gene copy-number and that more than 6 copies of CYP24A1 correlated positively with CYP24A1 mRNA expression suggestive of a causal relationship. No differences in CYP24A1 promoter methylation were found between tumor tissue and adjacent mucosa from the same patient or between tissues with high or low mRNA expression, thus excluding DNA hypomethylation as a possible cause of CYP24A1 overexpression in CRC. Furthermore, mRNA expression of several factors involved in replication licensing positively correlated with CYP24A1 mRNA expression, raising the possibility that CYP24A1 overexpression might favor increased proliferation in tumors by suppressing local 1,25-D3 levels. We conclude that high copy-number gain is a key determinant of CYP24A1 overexpression in CRC. Other postulated causes of CYP24A1 overexpression including promoter hypomethylation and enhanced VDR and/or RXR expression do not appear to be involved. What’s new? Recently, it has been suggested that the association between colorectal cancer and reduced levels of circulating vitamin D may be related to overexpression of the vitamin D-catabolizing enzyme, CYP24A1 in the tumor. In this search for a mechanistic explanation, increased CYP24A1 gene copy number was associated with the enzyme’s overexpression in 60 percent of colorectal tumors, and expression was correlated strongly with proliferation markers. The findings suggest that CYP24A1 overexpression is likely to deplete tumor calcitriol (1,25-dihydroxyvitamin D3) levels, possibly increasing the proliferative potential of the tumors.
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影响因子：
3.6
作者：
Marik, Radharani;Fackler, MaryJo;Umbricht, Christopher B.
通讯作者：
Umbricht, Christopher B.
影响因子：
3.2
作者：
Horvath, Henrik C.;Lakatos, Peter;Kallay, Enikoe
通讯作者：
Kallay, Enikoe
影响因子：
3.1
作者：
Giaginis, Constantinos;Georgiadou, Maria;Theocharis, Stamatios
通讯作者：
Theocharis, Stamatios
DOI：
10.1124/jpet.106.115451
发表时间：
2007-03-01
影响因子：
3.5
作者：
Lechner, Daniel;Manhardt, Teresa;Cross, Heide S.
通讯作者：
Cross, Heide S.
影响因子：
11.2
作者：
Luo W;Karpf AR;Deeb KK;Muindi JR;Morrison CD;Johnson CS;Trump DL
通讯作者：
Trump DL