A Role for Progesterone-Regulated sFRP4 Expression in Uterine Leiomyomas

J Clin Endocrinol Metab. 2017 Sep 1;102(9):3316-3326. doi: 10.1210/jc.2016-4014.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biopsy, Needle
  • Blotting, Western
  • Cell Proliferation / genetics
  • Disease Progression
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Immunohistochemistry
  • Leiomyoma / genetics*
  • Leiomyoma / pathology
  • Myocytes, Smooth Muscle / physiology
  • Progesterone / metabolism*
  • Promoter Regions, Genetic / genetics
  • Proto-Oncogene Proteins / genetics*
  • RNA, Messenger / metabolism
  • Real-Time Polymerase Chain Reaction / methods
  • Role
  • Uterine Neoplasms / genetics*
  • Uterine Neoplasms / pathology

Substances

  • Proto-Oncogene Proteins
  • RNA, Messenger
  • SFRP4 protein, human
  • Progesterone