Lack of functional and expression homology between human and mouse aldo-keto reductase 1C enzymes: implications for modelling human cancers
Lack of functional and expression homology between human and mouse aldo-keto reductase 1C enzymes: implications for modelling human cancers
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DOI：
10.1186/1476-4598-8-121
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发表时间：
2009-12-14
期刊：
影响因子：
37.3
通讯作者：
Bunce, Chris M.
中科院分区：
文献类型：
--
作者：
Velica, Pedro;Davies, Nicholas J.;Bunce, Chris M.
背景资料：近年来，醛酮还原酶（AKR）1C亚家族的酶与前列腺癌、乳腺癌、子宫内膜癌和白血病的进展有关。这是由于AKR 1C酶能够以组织特异性方式修饰雄激素、雌激素、孕酮和前列腺素（PG），调节核受体的活性和其他下游效应。支持AKR 1C酶在癌症中的作用的证据主要来自对患者或永生化细胞系的分离原代细胞的研究。小鼠是使用敲除或过表达菌株进行体内研究的理想生物体。然而，人类和小鼠之间AKR 1C酶的功能保守性还有待描述。在这项研究中，我们对四个人进行了表征和比较，（AKR 1C 1、-1C2、-1C3和-1C4）和八种鼠（AKR 1C 6、-1C12、-1C13、-1C14、-1C18、-1C19、-1C20和-1C21）同种型在它们的发生、底物偏好和组织分布方面的差异。我们发现人类和小鼠AKR 1C酶之间的不同进化反映了不同的底物偏好。鼠酶不进行前列腺素（PG）D-2的11 β-酮还原，这是一种对人AKR 1C 3具有特异性的活性，在促进白血病细胞存活方面很重要。相反，鼠AKR 1C 6能够进行PGE（2）的9-酮还原，这是人类同种型中不存在的活性。然而，减少的关键类固醇雄烯二酮，5 α-双氢睾酮，孕酮和雌酮被发现在小鼠亚型。然而，与人类不同的是，没有AKR 1C亚型检测到小鼠前列腺，睾丸，子宫和造血progenitors.Conclusions：这项研究暴露显着缺乏人类和小鼠AKR 1C酶之间的系统发育和功能同源性。因此，我们得出结论，小鼠不适合模拟AKR 1C在人类癌症和白血病中的作用。
Background: Over recent years, enzymes of the aldo-keto reductase (AKR) 1C subfamily have been implicated in the progression of prostate, breast, endometrial and leukemic cancers. This is due to the ability of AKR1C enzymes to modify androgens, estrogens, progesterone and prostaglandins (PGs) in a tissue-specific manner, regulating the activity of nuclear receptors and other downstream effects. Evidence supporting a role for AKR1C enzymes in cancer derives mostly from studies with isolated primary cells from patients or immortalized cell lines. Mice are ideal organisms for in vivo studies, using knock-out or over-expression strains. However, the functional conservation of AKR1C enzymes between human and mice has yet to be described.Results: In this study, we have characterized and compared the four human (AKR1C1,-1C2, -1C3 and -1C4) and the eight murine (AKR1C6, -1C12, -1C13, -1C14, -1C18, -1C19, -1C20 and -1C21) isoforms in their phylogeny, substrate preference and tissue distribution. We have found divergent evolution between human and murine AKR1C enzymes that was reflected by differing substrate preference. Murine enzymes did not perform the 11 beta-ketoreduction of prostaglandin (PG) D-2, an activity specific to human AKR1C3 and important in promoting leukemic cell survival. Instead, murine AKR1C6 was able to perform the 9-ketoreduction of PGE(2), an activity absent amongst human isoforms. Nevertheless, reduction of the key steroids androstenedione, 5 alpha-dihydrotestosterone, progesterone and estrone was found in murine isoforms. However, unlike humans, no AKR1C isoforms were detected in murine prostate, testes, uterus and haemopoietic progenitors.Conclusions: This study exposes significant lack of phylogenetic and functional homology between human and murine AKR1C enzymes. Therefore, we conclude that mice are not suitable to model the role of AKR1C in human cancers and leukemia.