Expression of erythropoietin messenger ribonucleic acid in wild-type MED12 uterine leiomyomas under estrogenic influence: new insights into related growth disparities

Abstract

Objective: To determine factors that impact erythropoietin (EPO) production in leiomyomas. We have previously implicated EPO production in promoting the growth of some leiomyomas.

Design: The relationship between EPO messenger RNA (mRNA) expression and MED12 gene mutations or mRNA expression levels of high-mobility group AT-hook (HMGA) 1 and HMGA2 were analyzed. Effects of 10^-8 M 17β-E₂ on EPO mRNA expression were evaluated using leiomyoma cells grown in primary cultures.

Setting: Graduate school of medicine.

Patient(s): Patients with leiomyoma.

Intervention(s): We used tissue samples and clinical data of 108 patients with leiomyomas to analyze the relation between EPO mRNA expression and MED12 mutation. Tissue samples from another 10 patients with leiomyomas were collected for in vitro experimentation using primary cultures of leiomyoma and myometrial cells.

Main outcome measure(s): Relations between EPO mRNA expression, MED12 exon 2 mutation, and HMGA1/HMGA2 mRNA expression levels in leiomyoma samplings, in addition to effects of estrogen (E) on EPO mRNA expression in cultures of leiomyoma cells.

Result(s): The EPO mRNA level was threefold higher in leiomyomas with wild-type (vs. mutated) MED12 genes. There was no correlation between EPO and HMGA1 or HMGA2 mRNA expression levels. In wild-type MED12 leiomyomas only, E₂ treatment produced a twofold increase in EPO mRNA expression, whereas mutated MED12 leiomyomas were unaffected.

Conclusion(s): The EPO mRNA expression increased significantly after E₂ treatment only in leiomyomas lacking MED12 mutations. In conjunction with prior evidence linking EPO mRNA expression levels and tumor size, E₂-stimulated EPO mRNA expression may explain the marked growth disparities seen in these tumors.

Keywords: MED12; Uterine leiomyoma; erythrocytosis; erythropoietin; estrogen.