醛固酮瘤中醛固酮合成相关酶与相应调节基因表达的变化

Expression of aldosterone synthesis related enzyme and associated regulatory factor genes in aldosterone-producing adenoma

目的比较醛固酮瘤(APA)与正常肾上腺组织的基因表达谱,探讨醛固酮合成过程的差异与可能的调节异常。方法以术后病理学检查确诊为APA的组织标本(APA组,n=10)及正常肾上腺组织(对照组,n=7)作为研究对象。提取两种组织的总RNA,合成生物素标记的探针cRNA,与载有一组靶基因的基因表达谱芯片杂交;通过扫描荧光强度,计算机软件分析,得到两种组织的表达差异基因;对异常表达靶基因进行Real-time PCR验证。结果与对照组相比,APA组有97个基因表达上调,168个基因表达下调;醛固酮合成路径中,仅CYP11B2表达显著上调;生理性调节醛固酮合成的因子中,CYB5A、CYP17A1、DUSP1、HMGCR表达下调,RENBP和NR1H2表达上调;皮质醇合成关键酶CYP17A1表达被抑制。结论在APA的醛固酮合成路径相关酶与调节因子中,CYP11B2可能是关键合成酶;多数生理性调节因子被抑制,提示存在肿瘤性调节因素。

Objective To investigate the discrepancy of aldosterone synthesis process and potential regulation abnormality between aldosterone-producing adenoma （APA） and normal adrenal （NA） with microarray. Methods cRNA probes labelled with biotin were prepared from mRNA of APAs （APA group, n = 10） or NAs （control group, n = 7）. The probes were hybridized with oligonucleotide microarray of target gene expression profile. Expression levels were read from the fluorescent intensity scanned. The difference of gene expression profile was analyzed by computer software. Differentially expressed genes were verified by real-time RT-PCR. Results Compared with control group, 97 genes were up-regulated and 168 genes were down-regulated in APA group. In the genes related to steroid hormone synthesis, only CYPllB2 was significantly up-regulated. In the physiologic regulators of aldosterone synthesis, CYBSA, CYP17A1, DUSP1 and HMGCR were down-regulated, while RENBP and NR1H2 were up-regulated. As a key enzyme in the biosynthesis of cortisol, the expression of CYP17A1 gene was inhibited. Conclusion Among the aldosterone synthesis related enzyme and corresponding regulatory genes in APA, CYP11B2 may be a key synthetase, and the suppressed physiologic regulators of aldosterone synthesis may indicate the existence of neoplastic modulation.