A Role for Progesterone-Regulated sFRP4 Expression in Uterine Leiomyomas

作者：Delaney Meaghan A; Wan Ying Wooi; Kim Gyoung Eun; Creighton Chad J; Taylor Margaret G; Masand Ramya; Park Andrew; Valdes Cecilia; Gibbons William; Liu Zhandong; Anderson Matthew L^*

来源：Journal of Clinical Endocrinology & Metabolism, 2017, 102(9): 3316-3326.

DOI：10.1210/jc.2016-4014

Context: Despite progesterone's key role in uterine smooth muscle tumorigenesis, the mechanisms by which it promotes the growth of uterine leiomyomas remain poorly understood.
Objective: The aim of this study was to identify gene products mediating the effects of progesterone in uterine leiomyomas.
Design: Gene expression profiling was used to identify putative progesterone-regulated genes differentially expressed in uterine leiomyomas, which were then studied in vitro.
Methods: 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.
Results: 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.
Conclusions: 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.

• 出版日期2017-9