A Role for Progesterone-Regulated sFRP4 Expression in Uterine Leiomyomas.
A Role for Progesterone-Regulated sFRP4 Expression in Uterine Leiomyomas.
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DOI：
10.1210/jc.2016-4014
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发表时间：
2017-09-01
期刊：
影响因子：
--
通讯作者：
Anderson ML
中科院分区：
文献类型：
--
作者：
Delaney MA;Wan YW;Kim GE;Creighton CJ;Taylor MG;Masand R;Park A;Valdes C;Gibbons W;Liu Z;Anderson ML
尽管孕激素在子宫平滑肌肿瘤发生中起关键作用，但其促进子宫平滑肌瘤生长的机制仍知之甚少。本研究的目的是确定基因产物介导的孕激素在子宫肌瘤的影响。基因表达谱被用来确定推定的甾体调节基因在子宫肌瘤中的差异表达，然后在体外进行研究。用Illumina WG BeadChip（2.6版）全面分析基因表达，并用整合已知蛋白质-蛋白质相互作用的生物信息学算法进行分析。通过染色质免疫沉淀-定量聚合酶链反应（ChIP-qPCR）询问孕酮受体（PR）的基因组结合位点。小干扰RNA用于研究原代细胞系中的基因功能。我们的分析确定分泌型卷曲相关蛋白4（sFRP 4）是与PR激活功能相关的关键基因产物，其在平滑肌瘤中的表达比子宫肌层高2.6倍（n = 26，P < 0.01），在月经周期的增殖期高2.5倍（n = 26，P < 0.01）。通过ChIP-qPCR观察到PR与sFRP 4启动子之间的直接结合。在来源于平滑肌瘤的原代培养物中也观察到sFRP 4的稳健过表达。孕酮优先抑制sFRP 4的表达和分泌在平滑肌瘤培养物中的剂量依赖性方式致敏的雌二醇。sFRP 4的敲低抑制子宫肌层和平滑肌瘤的原代培养物的增殖和凋亡。sFRP 4的过表达是平滑肌瘤的一个强有力的、甾体酮调节的特征，其增加平滑肌增殖。需要更多的工作来阐明孕酮调节sFRP 4表达的能力如何促进子宫平滑肌肿瘤的发生。通过研究随月经期变化的基因表达模式，我们发现sFRP 4的过表达是平滑肌瘤的一种甾体调节特征，可调节平滑肌增殖。
Despite progesterone’s key role in uterine smooth muscle tumorigenesis, the mechanisms by which it promotes the growth of uterine leiomyomas remain poorly understood. The aim of this study was to identify gene products mediating the effects of progesterone in uterine leiomyomas. Gene expression profiling was used to identify putative progesterone-regulated genes differentially expressed in uterine leiomyomas, which were then studied in vitro. Gene expression was comprehensively profiled with the Illumina WG BeadChip (version 2.6) and analyzed with a bioinformatic algorithm that integrates known protein–protein interactions. Genomic binding sites for progesterone receptor (PR) were interrogated by chromatin immunoprecipitation—quantitative polymerase chain reaction (ChIP-qPCR). Small interfering RNA was used to study gene function in primary cell lines. Our analyses identified secreted Frizzled-related protein 4 (sFRP4) as a key gene product functionally linked to PR activation whose expression was 2.6 times higher in leiomyomas than myometrium (n = 26, P < 0.01) and 2.5 times higher during the proliferative phase of the menstrual cycle (n = 26, P < 0.01). Direct binding between PR and sFRP4 promoter was observed by ChIP-qPCR. Robust overexpression of sFRP4 was also observed in primary cultures derived from leiomyoma. Progesterone preferentially inhibited sFRP4 expression and secretion in leiomyoma cultures in a dose-dependent manner sensitized by estradiol. Knockdown of sFRP4 inhibited proliferation and apoptosis in primary cultures of both myometrium and leiomyoma. Overexpression of sFRP4 is a robust, progesterone-regulated feature of leiomyomas that increases smooth muscle proliferation. More work is needed to elucidate how progesterone’s ability to modulate sFRP4 expression contributes to uterine smooth muscle tumorigenesis. Studying patterns of gene expression that vary by menstrual phase, we found that overexpression of sFRP4 is a progesterone-regulated feature of leiomyomas that regulates smooth muscle proliferation.
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NTR模块：netrins、分泌型frizzled相关蛋白和I型胶原蛋白C蛋白酶增强蛋白的结构域与金属蛋白酶组织抑制剂同源
影响因子：
8
作者：
Bányai, L;Patthy, L
通讯作者：
Patthy, L
影响因子：
3.7
作者：
Ono M;Qiang W;Serna VA;Yin P;Coon JS 5th;Navarro A;Monsivais D;Kakinuma T;Dyson M;Druschitz S;Unno K;Kurita T;Bulun SE
通讯作者：
Bulun SE
影响因子：
6
作者：
Muley, Ajit;Majumder, Syamantak;Chatterjee, Suvro
通讯作者：
Chatterjee, Suvro
影响因子：
3.6
作者：
Tanwar, Pradeep S.;Lee, Ho-Joon;Teixeira, Jose M.
通讯作者：
Teixeira, Jose M.
影响因子：
6.7
作者：
Ono M;Yin P;Navarro A;Moravek MB;Coon V JS;Druschitz SA;Gottardi CJ;Bulun SE
通讯作者：
Bulun SE