Increased expression of type 2 3α-hydroxysteroid dehydrogenase/type 5 17β-hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma
Increased expression of type 2 3α-hydroxysteroid dehydrogenase/type 5 17β-hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma
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DOI：
10.1677/erc.1.01048
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发表时间：
2006-03-01
影响因子：
3.9
通讯作者：
Lin, HK
中科院分区：
文献类型：
--
作者：
Fung, KM;Samara, ENS;Lin, HK
2型3α-羟基类固醇脱氢酶(3α-HSD)是一种多功能酶，具有3α、17β和20α-HSD以及前列腺素(PG)F合成酶活性，催化雄激素、雌激素、孕激素和前列腺素代谢。23型α-HSD是从人前列腺中克隆的，是醛酮还原酶(AKR)超家族的成员，命名为AKR1C3。在雄激素靶组织中，如前列腺，AKR1C3催化Delta(4)-雄烯-3，17-二酮转化为睾酮，5(x-二氢睾酮转化为5α-雄烯-3α，17β-二醇(3α-diol)和3(x-diol转化为雄酮)。因此，AKR1C3可能调节雄激素的平衡，从而调节这些组织中雄激素受体的反式激活。组织分布研究表明，AKR1C3转录本在人前列腺中高表达。为了检测AKR1C3蛋白在前列腺中的表达和分布，我们提出了一种特异性识别AKR1C3的单抗。这种抗体使我们能够将AKR1C3与人类组织中的其他AKR1C家族成员区分开来。免疫印迹分析表明，在原代培养的前列腺上皮细胞和LNCaP前列腺癌细胞中，该单抗与一种蛋白质结合。用该抗体对人前列腺进行免疫组织化学染色，在正常间质和平滑肌细胞、神经周围细胞、尿路上皮(移行)细胞和内皮细胞中检测到强烈的核免疫反应。正常前列腺上皮细胞仅呈微弱免疫反应或阴性。11例前列腺癌中有9例免疫反应阳性。AKR1C3免疫反应性的不同程度增加也显示在前列腺癌的非肿瘤性改变中，包括慢性炎症、萎缩和尿路上皮(移行)细胞化生。我们得出结论，AKR1C3的高表达与前列腺癌密切相关。虽然AKR1C3在前列腺癌中的生物学意义尚不清楚，但AKR1C3可能与雄激素和/或前列腺素对前列腺上皮细胞的营养作用有关。
Type 2 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) is a multi-functional enzyme that possesses 3 alpha-, 17 beta- and 20 alpha-HSD, as well as prostaglandin (PG) F synthase activities and catalyzes androgen, estrogen, progestin and PG metabolism. Type 2 3 alpha-HSD was cloned from human prostate, is a member of the aldo-keto reductase (AKR) superfamily and was named AKR1C3. In androgen target tissues such as the prostate, AKR1C3 catalyzes the conversion of Delta(4)-androstene-3,17-dione to testosterone, 5(x-dihydrotestosterone to 5 alpha-androstane-3 alpha,17 beta-diol (3 alpha-diol), and 3(x-diol to androsterone. Thus AKR1C3 may regulate the balance of androgens and hence transactivation of the androgen receptor in these tissues. Tissue distribution studies indicate that AKR1C3 transcripts are highly expressed in human prostate. To measure AKR1C3 protein expression and its distribution in the prostate, we raised a monoclonal antibody specifically recognizing AKR1C3. This antibody allowed us to distinguish AKR1C3 from other AKR1C family members in human tissues. Immunoblot analysis showed that this monoclonal antibody binds to one species of protein in primary cultures of prostate epithelial cells and in LNCaP prostate cancer cells. Immunohistochemistry with this antibody on human prostate detected strong nuclear immunoreactivity in normal stromal and smooth muscle cells, perineurial cells, urothelial (transitional) cells, and endothelial cells. Normal prostate epithelial cells were only faintly immunoreactive or negative. Positive immunoreactivity was demonstrated in primary prostatic adenocarcinoma in 9 of 11 cases. Variable increases in immunoreactivity for AKR1C3 was also demonstrated in non-neoplastic changes in the prostate including chronic inflammation, atrophy and urothelial (transitional) cell metaplasia. We conclude that elevated expression of AKR1C3 is highly associated with prostate carcinoma. Although the biological significance of elevated AKR1C3 in prostatic carcinoma is uncertain, AKR1C3 may be responsible for the trophic effects of androgens and/or PGs on prostatic epithelial cells.