PLIN2 Functions As a Novel Link between Progesterone Signaling and Metabolism in Uterine Leiomyoma Cells

Ijeoma Okeigwe, Serdar Bulun, Shimeng Liu, Alfred W. Rademaker, John S. Coon, Stacy Kujawa, Jared Robins, Ping Yin

Research output: Contribution to journalArticle

Abstract

Context: Uterine leiomyoma (fibroids) are the most common tumors in women. Recently, perilipin-2 (PLIN2) was identified as a critical target gene of the progesterone receptor; however, its function in the pathogenesis of fibroids is unknown. Objective: To determine the function of PLIN2 in leiomyoma cells. Design: Tissue and primary cells from leiomyoma and myometrium were analyzed. PLIN2 function in leiomyoma was assessed using small interfering RNA. RNA-sequencing was performed to identify genome-wide effects of PLIN2 depletion. Metabolic activity was measured using the Seahorse XF96 analyzer. Real-time quantitative PCR and immunoblotting were also performed. Setting: Laboratory. Patients or Other Participants: Forty-one premenopausal women undergoing surgery for fibroids. Main Outcome Measures: Gene expression, oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and cell proliferation. Results: PLIN2 gene expression was 2.4-fold lower in leiomyoma compared with adjacent myometrium, suggesting a link between PLIN2 deficiency and fibroids. A total of 3877 genes were differentially expressed after PLIN2 knockdown. Gene ontology analysis identified metabolism as the second-highest biological process affected by PLIN2 depletion. OCR (mitochondrial respiration) and ECAR (glycolysis) were significantly upregulated after PLIN2 knockdown; PLIN2-depleted cells had a greater basal metabolic activity and higher metabolic stress response. Cell proliferation was also significantly increased after PLIN2 knockdown. Conclusions: PLIN2 depletion increases mitochondrial respiration and glycolysis, suggesting that PLIN2 is a critical regulator of metabolic function in leiomyoma cells. PLIN2 deficiency also reprograms leiomyoma cells to a proproliferative phenotype. These findings introduce metabolomics as an area to explore to better understand leiomyoma tumorigenesis.

Original languageEnglish (US)
Pages (from-to)6256-6264
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Volume104
Issue number12
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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