Leiomyoma and myometrial gene expression profiles and their responses to gonadotropin-releasing hormone analog therapy
Leiomyoma and myometrial gene expression profiles and their responses to gonadotropin-releasing hormone analog therapy
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DOI：
10.1210/en.2004-1384
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发表时间：
2005-03-01
期刊：
影响因子：
4.8
通讯作者：
Chegini, N
中科院分区：
文献类型：
--
作者：
Luo, XP;Ding, L;Chegini, N
采用基因微阵列技术表征平滑肌瘤和匹配的肌层在生长过程中的分子环境、GnRH类似物（GnRHa）治疗的反应以及GnRHa对平滑肌瘤和子宫平滑肌细胞（LSMC和MSMC）原代培养的直接作用。对基因表达值进行无监督分析和有监督分析，并对R编程进行统计学分析，错误发现率P小于或等于0.02，在未治疗组和GnRHa治疗组中分别鉴定出平滑肌瘤和子宫肌层中153个和122个差异表达基因。与未治疗组相比，这些组织中有170和164个基因的表达受到GnRHa治疗的影响。GnRHa （0.1 muM）以时间依赖的方式（2、6和12 h）靶向281个基因（P <或等于0.005）在LSMC和MSMC中表达，其中48个基因与GnRHa处理的组织共同存在。功能注释将这些基因指定为转录、翻译、信号转导、结构活动和细胞凋亡等过程的关键调节因子。我们验证了IL-11、早期生长反应3、tgf - β诱导因子、tgf - β诱导的早期基因反应、CITED2 （cAMP反应元件结合蛋白结合蛋白/p300与ed富尾相互作用的反激活因子）、Nur77、生长停滞特异性1、p27、p57和G蛋白偶联受体激酶5的表达，它们代表了细胞因子、常见转录因子、细胞周期调节因子和信号转导。在组织水平和LSMC和MSMC中对GnRHa时间依赖性作用的响应，使用实时PCR， Western blotting和免疫组织化学。总之，通过不同的互补方法，我们表征了平滑肌瘤和子宫肌层的分子指纹图谱，并鉴定了几个以前未被识别的基因作为GnRHa作用的靶点，这意味着这些基因的局部表达和激活可能代表了在生长和GnRHa诱导的消退过程中平滑肌瘤和子宫肌层环境的差异特征。
Gene microarray was used to characterize the molecular environment of leiomyoma and matched myometrium during growth and in response to GnRH analog (GnRHa) therapy as well as GnRHa direct action on primary cultures of leiomyoma and myometrial smooth muscle cells (LSMC and MSMC). Unsupervised and supervised analysis of gene expression values and statistical analysis in R programming with a false discovery rate of P less than or equal to 0.02 resulted in identification of 153 and 122 differentially expressed genes in leiomyoma and myometrium in untreated and GnRHa- treated cohorts, respectively. The expression of 170 and 164 genes was affected by GnRHa therapy in these tissues compared with their respective untreated group. GnRHa (0.1 muM), in a time-dependent manner (2, 6, and 12 h), targeted the expression of 281 genes (P less than or equal to 0.005) in LSMC and MSMC, 48 of which genes were found in common with GnRHa-treated tissues. Functional annotations assigned these genes as key regulators of processes involving transcription, translational, signal transduction, structural activities, and apoptosis. We validated the expression of IL-11, early growth response 3, TGF-beta-induced factor, TGF-beta-inducible early gene response, CITED2 (cAMP response element binding protein-binding protein/p300-interacting transactivator with ED-rich tail), Nur77, growth arrest-specific 1, p27, p57, and G protein-coupled receptor kinase 5, representing cytokine, common transcription factors, cell cycle regulators, and signal transduction, at tissue levels and in LSMC and MSMC in response to GnRHa time-dependent action using real-time PCR, Western blotting, and immunohistochemistry. In conclusion, using different, complementary approaches, we characterized leiomyoma and myometrium molecular fingerprints and identified several previously unrecognized genes as targets of GnRHa action, implying that local expression and activation of these genes may represent features differentiating leiomyoma and myometrial environments during growth and GnRHa-induced regression.